Elly's Story
The Orphan Drug Act defines rare diseases as those that affect less than 200,000 people in the United States. The European Union definition is slightly different, with diseases that affect no more than 1 in 2,000 people considered rare. Those numbers are difficult enough to comprehend, but there are also ultra-rare diseases that affect just 100 to 200 people—or fewer—worldwide. Unfortunately, many young children are experiencing rapid disease progression and limited time and opportunity to receive treatment.
The development of a new drug typically takes many years and billions of dollars. How, then, can parents receiving devastating diagnoses for their children have any chance of finding treatment in time? This blog series outlines the story of one family’s journey from diagnosis to administration of a novel gene replacement therapy 14 months later, and how they were supported by clinicians, researchers, hospitals, universities, and manufacturing organizations to make the seemingly impossible happen for their daughter.
The Krueger family’s journey of gene replacement therapy development began the day before Thanksgiving in 2023. They took 5-month-old Elly, their third child, to the pediatrician to investigate rapid onset of developmental delays, which included strange eye movements almost like her eyes were moving in her head. The evening was spent in the emergency room of Weill Cornell hospital with Elly undergoing every test imaginable, including a CAT scan and magnetic resonance imaging of her brain, an EKG, and visits from an ophthalmologist and neurologist. Everything appeared normal. After leaving a message for Dr. Zachary Grinspan, the lead on-call pediatric neurologist they went home around 3 AM expecting to return after the holiday weekend.
It was the first miracle for the Kruegers, according to Michelle, that Dr. Grinspan, a leading neurologist, was on call that day. He took time Thanksgiving afternoon to not only reach out, but after observing Elly’s eye movements via a video call, meet the family at the hospital for additional testing. He quickly determined she was experiencing focal seizures and infantile spasms and immediately began treating Elly with anti-seizure medications.
While the focal seizures quickly dissipated, the infantile spasms did not. They can randomly develop, resulting from structural issues such as brain tumors, or be due to a genetic disease. After several lines of treatment with no progress, it was clear Elly was suffering from something serious. Further imaging of her brain revealed no structural issues, and the diagnosis was discovered after full genome sequencing: Elly has a genetic mutation in the IRF2BPL gene, which causes Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS).
Dr. Grinspan immediately spent time researching the mutation and informed the Krueger’s an hour later that the mutation was ultra-rare, likely neurodegenerative, and there were no treatments or cure. The Kruegers’ immediate response was, instead of buckling under the devastating news, to fight to develop one.
They founded Elly’s Team, a faith-based foundation with a singular focus on translating medical research into treatment in record time and sought help from numerous quarters. The mother of a son with a different rare disease (who Michelle connected to through a friend of a friend) spent three hours teaching Michelle everything she knew about basic genetics, gene editing, gene replacement therapy, and drug repurposing. Networking also led Michelle and Dan to Rod and Marti at the RTW Foundation, which funds rare disease research, medical innovation, and local community collaborations. A connection that would be invaluable as the Krueger’s continued their journey, with the addition of Joe Katakowski (PhD, Director of Research) to their board, another miracle along the way.
The Kruegers also discovered Dr. Kathrin Meyer, who had miraculously already been working with funding for diseases in the IRF2BPL community. In her role as Chief Scientific Officer of Alcyone Therapeutics, and formally at Nationwide Childrens Hospital, Dr. Meyer was investigating possible treatment avenues for NEDAMSS as part of her research in mutations of the IRF2BPL genes. She, Dr. Grinspan, and experts at the RTW Foundation helped Michelle and Dan to ultimately prioritize three treatment options to pursue: drug repurposing, antisense oligonucleotides (ASOs) to target mRNA or gene addition therapy.
They first reached out to numerous biotech labs and drug developers regarding development of an ASO drug. The IRF2BPL gene presents unique challenges, including that it is a single-exon gene containing no introns and has many repeated sequences (GC-rich in particular), both of which make ASO development difficult. La Jolla Labs, experts in the design of RNA therapeutics, took on the project and after completing an in-depth project, unfortunately confirmed that this approach was not feasible.
In parallel, Michelle and Dan engaged with Unravel Biosciences, which used Elly’s RNA data to identify potential existing drugs that might alter her disease progression. From the list of generated candidates, five lead drugs were selected and are currently being evaluated in a disease-induced tadpole model.
The need became increasingly urgent as the Krueger’s learned over the first few months following Elly’s diagnosis that she fell into the group of children with a severe form of the disease, with progressive debilitation often leading to premature death. The severity of Elly’s disease was unfortunately further confirmed through a repeat MRI in June 2024 indicating brain development challenges and zero percentile head size. Despite many people telling Dan and Michelle that developing a gene replacement therapy would take at least three to five years and $5 to 10 million, they forged ahead with support from Dr. Meyer and Dr. Grinspan, who understood the importance of speed and the need to find a way to go years faster and cheaper without sacrificing safety or efficacy.
The solution was to start developing a clinical manufacturing process at the same time that preclinical (proof-of-concept and safety) studies were being performed. While such an approach was financially risky, it would allow production of clinical material in the least amount of time possible and make it possible to administer the gene replacement therapy to Elly as soon as FDA approval was received.
The preclinical work, including proof of concept and safety studies, was performed at the University of Missouri under the auspices of Dr. J Andrea Sierra Delgado, a colleague of Dr. Meyer’s when they worked together at Nationwide Children’s Hospital and Dr. Smita Saxena, a world-renown neuroscientist and cellular assay specialist. First, the gene replacement therapy was shown to recover Elly’s patient-derived cells. Next, with no mouse model for the disease, Dr. Sierra Delgado and Dr. Saxena confirmed these results in disease-induced wild-type mice, while the team from Unravel confirmed efficacy in mutated tadpoles simultaneously. Safety studies to support an investigational new drug (IND) application were performed in healthy mice and pigs at the University of Missouri.
The gene replacement therapy designed by Dr. Meyer and her team in collaboration with Elly’s Team is based on an adeno-associated viral (AAV) vector. Production of the plasmid DNA needed to manufacture the vector started just four months following Elly’s diagnosis (in June 2024). The material was provided to Andelyn Biosciences in September, who leveraged their AAV Curator® platform production process and extensive know-how in AAV manufacturing to develop a process and produce clinical material by January 2, 2025.
The speed at which all this work was accomplished reflects the commitment of all involved to get treatment for Elly as quickly as possible. The standard market pace of anywhere from 2 to 10 years for funding, development and commercialization was too much of a risk.
Because of this commitment to beat the clock, Elly was dosed on April 3, 2025, a mere 14 months after her diagnosis and 10 months after their pursuit of gene replacement therapy began. A timeline, according to Michelle, “that was only accomplished due to relentless effort, a lot of prayer, divine intervention and a series of miracles”.
The success of this multifaceted team shows what can be accomplished with grit, determination, and the will to succeed. Michelle also acknowledges that developing this gene replacement therapy treatment for Elly in such a short time was made possible by Michelle and Dan’s network. Those factors enabled them to reach the right people and raise funds to supplement the money and continue to invest into the foundation personally. The Kruegers’ goal is that all patients suffering from this disease will have access to treatment in the future.
The procedure went smoothly, and so far, Elly is doing well. Dan, Michelle, Dr. Grinspan, Dr. Meyer, and everyone at the RTW Foundation, Andelyn Biosciences, and the University of Missouri are anxiously waiting to see how she responds. All are hopeful.
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The existence of Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) and the role played by mutations of the IRF2BPL (interferon regulatory factor 2 binding protein-like) gene in the disease were first outlined only in 2018. Much is still not known about the disease.
Although NEDAMSS is a genetic disorder, it is usually not inherited. The IRF2BPL gene is believed to be important for developing and maintaining healthy brain cells. It encodes a protein that is almost exclusively located in the nucleoplasm and acts as a transcriptional regulator.
Mutations of IRF2BPL can be rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel). The different variants can result in different problems, including developmental delays, seizures, movement disorders, and regression of capabilities, all of which can occur to varying degrees depending on the specific mutation. The mutations cause aberrant sequestration of the protein to the cytoplasm, preventing its proper functioning in the nucleus. While symptoms can appear in the first months of life, for most children they appear in early childhood after meeting normal developmental milestones.
Greater understanding of NEDAMSS and its disease pathways has been difficult to obtain due to the very small number of patients so far identified with the condition, the limited information available regarding natural progression of the disease, the lack of direct correlations between different variants and the severity and age of onset of the disease, the lack of neural tissues available for study, no access to well-defined in vitro and animal models, and lack of funding.
Much of the knowledge gained about IRF2BPL mutations linked to NEDAMSS was generated by Dr. Kathrin Meyer and colleagues working at Nationwide Children’s Hospital (NCH). Dr. Meyer is deeply invested in rare disease research and had previously been approached by patient organizations before Elly’s diagnosis to investigate NEDAMSS. She, with the assistance of various collaborators, had performed extensive in vitro studies to characterize disease processes and test potential therapeutic avenues. Initial work with adeno-associated viral (AAV) vectors in patient cells was also performed with preliminary encouraging results. By the time Elly Krueger received her NEDAMSS diagnosis, Dr. Meyer felt strongly that gene replacement therapy was a potential option, but nothing was guaranteed.
Connecting with Dr. Meyer was key to the effort being pursued by Dan and Michelle to develop a treatment for Elly fast enough to make a real difference for their daughter. She was confident that with enough resources they could rapidly and safely produce the gene replacement therapy.
The first step was to avoid the need to raise government funding (a process that can take two years or more and requires extensive pre-existing preclinical data). Thanks to their extensive network, the Kruegers were able to fundraise rapidly with great success. The second key was to perform various aspects of the preclinical work, process development, and manufacturing in parallel rather than sequentially, which further and dramatically shortened the timeline. While helping to reduce the overall development cost, however, this approach introduced real financial risk to the Kruegers and their supporters, as manufacturing began even before the first safety studies or proof of concept studies were started.
Dan and Michelle recognized and accepted the risk, knowing that time was of the essence for Elly. They also were highly focused on moving the project forward. They quickly made decisions based on recommendations provided by various advisors, rather than becoming overwhelmed and involving too many parties with too many differing opinions, which can impede progress.
Preclinical work was completed by the team at NextGen Precision Health, University of Missouri with Dr. Meyers input and oversight. Dr. J Andrea Sierra Delgado moved from NCH to the University of Missouri to join Dr. Saxenas team who was setting up lab space at this new translational institute at that time. It is an incredible achievement of the team to complete the entire project in less than one year despite Dr. Sierra Delgado having to move states to continue the NEDAMSS research.
Proof-of-concept studies were performed with Elly’s cells, and mice, while the company Unravel Biosciences simultaneously performed experiments in tadpoles. Because a well-characterized mouse model of the disease was not available, the researchers used AAV to induce a disease state in healthy mice and treated some of them with the gene replacement therapy. While those that did not receive the treatment experienced loss of physical functionality, the mice treated remained healthy.
In addition to running proof-of-concept and safety studies in parallel, Elly’s Team also made the decision to use pigs rather than rats or monkeys for the large-animal study. Pigs have been shown to reproduce the targeting of the gene replacement therapy virus used in this project and are a good large animal model to facilitate dose-escalation and establish safety in an animal more closely related to humans. They are also easier to handle and faster to breed. Furthermore, for this study, the team used the clinical grade Good Manufacturing Practice (GMP)-compliant material to ensure the results were obtained using the same product that would be used to dose Elly, a decision that was once again made for speed without sacrificing safety. Using valuable clinical material avoided any possibility of needing to perform additional extrapolation studies if there were differences in the research and cGMP batches, which could have significantly delayed Elly’s dosing.
The gene replacement therapy is based on an AAV9 vector designed with elements commonly found in other gene therapies already shown to be safe in clinical applications. AAV9 vectors are widely used for the treatment of genetic neurodegenerative diseases because they travel to brain tissue when injected through blood or spinal fluid. The vector developed to treat NEDAMSS patients delivers a healthy IRF2BPL copy that results in production of a healthy IRF2BPL protein to increase the amount of healthy protein in the nucleoplasm where it can function correctly.
One of the factors making gene replacement therapy attractive for NEDAMSS, according to Dr. Meyer, is the fact that most patients produce small amounts of normal protein. Thus, when the body begins producing the protein that is introduced with the therapy, the immune system does not recognize it as a foreign substance, reducing the likelihood of undesired immune responses—a complication observed with some other gene therapies.
The clinical material was produced at Andelyn Biosciences. Dr. Meyer has worked with Andelyn on many clinical programs over the years and sees the company as a trustworthy resource that reliably provides safe, effective material at speed. In this case, the clinical grade (GMP) gene replacement therapy for Elly was produced and fully released for use in early January 2025. However, to gain more time, Dr. Meyer requested Andelyn to release the material earlier, so it could be tested “at risk” in line with the University of Missouri. This allowed animal studies to commence and be performed in parallel to final release testing. The large-animal safety studies were immediately initiated, and once the data was available, an investigational new drug (IND) application for dosing of Elly with the gene replacement therapy candidate was submitted to the FDA on February 17th.
One important decision made by the entire team regarded the way the new gene replacement therapy would be administered. With neurodegenerative diseases, it is essential that the gene replacement therapy be delivered to and stay in the brain. An effective way to achieve this goal is to inject the therapy into the cerebrospinal fluid surrounding the brain and spinal cord via a method known as Intracisterna Magna injection (ICM). Working with Weill Cornell, this protocol was established as the best-case scenario for the delivery of Elly’s gene replacement therapy.
Carrying this forward, modeling work was done by Dr. Meyer’s to identify the best formulation and safety approach to make this type of delivery possible. In addition to animal and cellular studies, her team at Alcyone Therapeutics used the proprietary FalconTM Precision Delivery Platform to optimize drug delivery parameters for Elly. The team generated a so called “digital twin” – an MRI based computer model of Elly’s brain to help optimize the injection parameters with the goal to allow more drug to spread efficiently around the brain instead of leaking into the peripheral organs.
The IND-application was approved following the 30-day review period of the FDA, and Elly was dosed 14 months from her diagnosis at Weil Cornell Hospital on April 3, 2025. The willingness of the hospital administration to support the Kruegers’ efforts to treat Elly with an experimental gene replacement therapy is an important aspect of this story that cannot be dismissed. Similarly, the open-minded approach to Elly’s treatment taken by her pediatric neurologist Dr. Zachary Grinspan is another.
Now the family and the extended team involved in bringing this new gene replacement therapy to Elly are trying to manage expectations while hoping for the best. There is still a great deal yet unknown about the disease, how the gene replacement therapy is distributed in the brain, whether there will be immune issues, or specifically in Elly’s case, how many brain cells exist that can still respond to treatment. Knowing that some degeneration has already occurred, the hope is the gene replacement therapy will at least slow down and ideally halt progression of the disease.
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Of the many important decisions Michelle and Dan Krueger had to make when pursuing the development and production of a novel gene replacement therapy for Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) was choosing the right contract development and manufacturing organization (CDMO) to manufacture the therapy.
After learning their 8-month-old daughter Elly suffered from a severe form of this ultra-rare neurodegenerative disease, the parents sought out Dr. Kathrin Meyer of Alcyone Therapeutics for her unique knowledge about the cause of NEDAMSS (mutations in the IRF2BPL, or interferon regulatory factor 2 binding protein-like, gene). She encouraged the Kruegers to explore different options and select the CMDO they felt would best meet their needs; there was quite a bit of competition.
Andelyn Biosciences was one of the first CDMOs the Kruegers considered due to the long-term relationship Dr. Meyer has with the company from her time working for Nationwide Children’s Hospital (NCH), from where Andelyn spun out of in 2020. Andelyn was initially formed to produce clinical trial material for physicians conducting gene therapy trials at NCH and today supports many global programs from early to late-stage development and commercial manufacturing.
According to CEO, Wade Macedone, the Andelyn team has much experience working on small projects and does not prioritize Big Pharma clients over emerging biotechs or foundations. In fact, the CDMO reserves a certain percentage of its capacity specifically to support nonprofits, including those involving a single patient and families seeking to access gene therapies for their children.
Mr. Macedone knows that it is not easy for parents like Dan and Michelle to trust an organization they do not know with the production of a novel treatment that will be administered to their child. During his first meeting with Michelle, therefore, he spent time sharing important questions that she should ask of different CDMO contenders, particularly regarding their experience in producing viral vectors used in clinical studies and working with parents focused on saving their children. The latter experience is important because interacting with parents with a severely ill child requires very different skills than those needed when dealing with drug developers.
Dan and Michelle ultimately chose Andelyn Biosciences, largely driven by their expertise, network, and technology. The Andelyn AAV Curator® platform for production of adeno-associated viral (AAV) vectors has been continuously curated over more than 15 years. This adherent platform includes a well-established cell line, well-understood upstream manufacturing and downstream purification processes, and proprietary fit-for-purpose analytical methods for process development and product release. The platform is also available for suspension processes as needed based on afflicted population and dosing required.
Andelyn's data-driven approach to process development leverages decades of production data to shorten timelines while still ensuring cost-effective and improved manufacturing processes. The Curator® platform is also highly predictable in terms of yield and quality and eliminates intellectual property concerns because the technology has all been developed internally. Furthermore, review of investigational new drug (IND) applications is streamlined as the referenced Drug Master Files (DMFs) have been reviewed and approved by the FDA previously, removing unnecessary hurdles and delays.
Another important enabler for the accelerated manufacturing of Elly’s gene replacement therapy was the willingness of Michelle and Dan to rely on Andelyn’s expertise, not disrupt progress with any preconceived ideas of what or how things should be done and listen to guidance regarding what they could do to help—and then follow through.
Effective collaboration and coordination with other service providers also made a difference in so rapidly developing a process and producing the gene replacement therapy for Elly. The DNA plasmids, which are critical raw materials for AAV vector production, were rapidly manufactured while Genezen quickly established a stability and compatibility study to ensure the manufactured clinical product was compatible with the materials of intended injection tools.
Collaboration was particularly crucial to successfully getting the plasmids to Andelyn. They were manufactured at an overseas site and were held up at customs when shipped to the United States. The Kruegers worked closely with Andelyn to get them released indicating, “The team moved mountains for us in getting the plasmids released to not miss our manufacturing start date. This was one of the first mountains Andelyn moved for us in our process, with many more to come”.
Providing rapid and cost-effective gene therapy manufacturing services is not the only way Andelyn is committed to helping families like the Kruegers. In addition to educating parents like Dan and Michelle about critical considerations when selecting a contract manufacturer, Andelyn also seeks to raise awareness and funds for the gene therapy and rare disease community. Many families face not only limited treatment options but lack access to necessary financial and other resources.
Andelyn hosts events like the annual FORE One Purpose golf tournament, the first of which was held in September 2024. When planning for this signature event, Mr. Macedone was seeking a family that could benefit from Andelyn Biosciences’ expertise and capabilities to serve as a great example of what courage, fortitude, and commitment can achieve. The Krueger family was the perfect fit. The $50,000 raised from the first tournament went to Elly’s Team, the foundation established by Michelle and Dan to support development of a cure for NEDAMSS. Planning is well underway for the 2025 event, which will take place on August 11th, 2025.
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A clinical-grade gene replacement therapy being developed, manufactured, and approved for treatment of Elly Krueger in just 10 months is nothing less than amazing.
Much of the success can be attributed to Dan and Michelle, who were constantly managing and coordinating the efforts of the many groups involved in getting treatment for Elly in time to make a difference. The Kruegers also recognize the roles played by all of those groups and many individuals who were so committed to Elly’s cause.
They are extremely grateful that Dr. Zachary Grinspan was on call on Thanksgiving of 2023. His neurological expertise, knowledge of gene therapy, and support for the Kruegers’ efforts to develop a treatment were immensely important. The initial evidence of Dr. Kathrin Meyers’ team showing that gene replacement therapy could potentially help Elly, coupled with her encouragement and network of resources, were also invaluable. The incredible dedication of the team at the University of Missouri to complete proof of concept and safety studies in an extremely fast timeline, and the willingness of the folks at Andelyn Biosciences to take calls at any time of day, enabled filing of the investigational new drug (IND) application with the Food and Drug Administration to proceed smoothly.
That so many different people and organizations were necessary to turn the concept of a gene replacement therapy for NEDAMSS into a reality highlights the complexity that families facing such a devastating diagnosis must overcome.
The Kruegers’ experience also clearly shows that when there is a will, there is a way, to accomplish what many in the industry profess to be impossible. Indeed, it does not have to take 5+ years and $5 million or more to develop every gene therapy. Finding access to a great team, being able to tell your story while illustrating grit and willingness to fight for your son or daughter, and knowledge of safe and effective strategies for accelerating preclinical studies and process development demonstrate that treatments can be made available in much less time and at much lower cost.
In 2024, the Kruegers participated in a charity event called Fore One Purpose, which featured Elly as the Impact Champion. The event raised more than $50,000 towards helping children with ultra rare IRF2BPL diseases and will take place again in August of 2025.
As the Kruegers and their extended team of supporters continue to observe Elly and eagerly wait to hear more about how she is responding to the gene replacement therapy, they are also making plans to continue efforts in support of others in the rare- and ultra-rare disease community.
Michelle and Dan issued a letter to the IRF2BPL community on their website in early May, introducing themselves and Elly’s Team and explaining the work they have done and how it was funded. They hosted a webinar, with Dr. Meyer and Dr. Grinspan, for the families in the community to further explain their path to treatment and the next steps. The manufacturing process developed by Andelyn Biosciences provided more than just the one dose needed to treat Elly. The Kruegers plan to expand the IND and clinical trial to treat more patients, but require continued fundraising to achieve this.
Dan and Michelle do not intend to stop there. Hundreds of thousands of children suffer from rare and ultra-rare neurodegenerative/neurodevelopmental and seizure-based diseases for which there currently are no treatments. They want to apply the experience they have gained developing the NEDAMSS gene replacement therapy for Elly—and the approach used to dramatically shorten the timeline for translating research into treatments—to helping these children and their families.
Having faced the devastating news of their daughter’s diagnosis and fought through the despair it engendered, Michelle and Dan have committed to continuing the fight not just for Elly, but for other parents that are not able to take this kind of action. “For those who have been given much, much is expected. Our despair has been replaced with a deep sense of purpose”, they say. They want to know that when families in the future receive an ultra-rare neurodegenerative disease diagnosis, such as NEDAMSS, they won’t have to hear that there is no cure and accept that as the final answer. They can fight for a path to treatment for their children.
Information about the gene therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.
The Orphan Drug Act defines rare diseases as those that affect less than 200,000 people in the United States. The European Union definition is slightly different, with diseases that affect no more than 1 in 2,000 people considered rare. Those numbers are difficult enough to comprehend, but there are also ultra-rare diseases that affect just 100 to 200 people—or fewer—worldwide. Unfortunately, many young children are experiencing rapid disease progression and limited time and opportunity to receive treatment.
The development of a new drug typically takes many years and billions of dollars. How, then, can parents receiving devastating diagnoses for their children have any chance of finding treatment in time? This blog series outlines the story of one family’s journey from diagnosis to administration of a novel gene replacement therapy 14 months later, and how they were supported by clinicians, researchers, hospitals, universities, and manufacturing organizations to make the seemingly impossible happen for their daughter.
The Krueger family’s journey of gene replacement therapy development began the day before Thanksgiving in 2023. They took 5-month-old Elly, their third child, to the pediatrician to investigate rapid onset of developmental delays, which included strange eye movements almost like her eyes were moving in her head. The evening was spent in the emergency room of Weill Cornell hospital with Elly undergoing every test imaginable, including a CAT scan and magnetic resonance imaging of her brain, an EKG, and visits from an ophthalmologist and neurologist. Everything appeared normal. After leaving a message for Dr. Zachary Grinspan, the lead on-call pediatric neurologist they went home around 3 AM expecting to return after the holiday weekend.
It was the first miracle for the Kruegers, according to Michelle, that Dr. Grinspan, a leading neurologist, was on call that day. He took time Thanksgiving afternoon to not only reach out, but after observing Elly’s eye movements via a video call, meet the family at the hospital for additional testing. He quickly determined she was experiencing focal seizures and infantile spasms and immediately began treating Elly with anti-seizure medications.
While the focal seizures quickly dissipated, the infantile spasms did not. They can randomly develop, resulting from structural issues such as brain tumors, or be due to a genetic disease. After several lines of treatment with no progress, it was clear Elly was suffering from something serious. Further imaging of her brain revealed no structural issues, and the diagnosis was discovered after full genome sequencing: Elly has a genetic mutation in the IRF2BPL gene, which causes Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS).
Dr. Grinspan immediately spent time researching the mutation and informed the Krueger’s an hour later that the mutation was ultra-rare, likely neurodegenerative, and there were no treatments or cure. The Kruegers’ immediate response was, instead of buckling under the devastating news, to fight to develop one.
They founded Elly’s Team, a faith-based foundation with a singular focus on translating medical research into treatment in record time and sought help from numerous quarters. The mother of a son with a different rare disease (who Michelle connected to through a friend of a friend) spent three hours teaching Michelle everything she knew about basic genetics, gene editing, gene replacement therapy, and drug repurposing. Networking also led Michelle and Dan to Rod and Marti at the RTW Foundation, which funds rare disease research, medical innovation, and local community collaborations. A connection that would be invaluable as the Krueger’s continued their journey, with the addition of Joe Katakowski (PhD, Director of Research) to their board, another miracle along the way.
The Kruegers also discovered Dr. Kathrin Meyer, who had miraculously already been working with funding for diseases in the IRF2BPL community. In her role as Chief Scientific Officer of Alcyone Therapeutics, and formally at Nationwide Childrens Hospital, Dr. Meyer was investigating possible treatment avenues for NEDAMSS as part of her research in mutations of the IRF2BPL genes. She, Dr. Grinspan, and experts at the RTW Foundation helped Michelle and Dan to ultimately prioritize three treatment options to pursue: drug repurposing, antisense oligonucleotides (ASOs) to target mRNA or gene addition therapy.
They first reached out to numerous biotech labs and drug developers regarding development of an ASO drug. The IRF2BPL gene presents unique challenges, including that it is a single-exon gene containing no introns and has many repeated sequences (GC-rich in particular), both of which make ASO development difficult. La Jolla Labs, experts in the design of RNA therapeutics, took on the project and after completing an in-depth project, unfortunately confirmed that this approach was not feasible.
In parallel, Michelle and Dan engaged with Unravel Biosciences, which used Elly’s RNA data to identify potential existing drugs that might alter her disease progression. From the list of generated candidates, five lead drugs were selected and are currently being evaluated in a disease-induced tadpole model.
The need became increasingly urgent as the Krueger’s learned over the first few months following Elly’s diagnosis that she fell into the group of children with a severe form of the disease, with progressive debilitation often leading to premature death. The severity of Elly’s disease was unfortunately further confirmed through a repeat MRI in June 2024 indicating brain development challenges and zero percentile head size. Despite many people telling Dan and Michelle that developing a gene replacement therapy would take at least three to five years and $5 to 10 million, they forged ahead with support from Dr. Meyer and Dr. Grinspan, who understood the importance of speed and the need to find a way to go years faster and cheaper without sacrificing safety or efficacy.
The solution was to start developing a clinical manufacturing process at the same time that preclinical (proof-of-concept and safety) studies were being performed. While such an approach was financially risky, it would allow production of clinical material in the least amount of time possible and make it possible to administer the gene replacement therapy to Elly as soon as FDA approval was received.
The preclinical work, including proof of concept and safety studies, was performed at the University of Missouri under the auspices of Dr. J Andrea Sierra Delgado, a colleague of Dr. Meyer’s when they worked together at Nationwide Children’s Hospital and Dr. Smita Saxena, a world-renown neuroscientist and cellular assay specialist. First, the gene replacement therapy was shown to recover Elly’s patient-derived cells. Next, with no mouse model for the disease, Dr. Sierra Delgado and Dr. Saxena confirmed these results in disease-induced wild-type mice, while the team from Unravel confirmed efficacy in mutated tadpoles simultaneously. Safety studies to support an investigational new drug (IND) application were performed in healthy mice and pigs at the University of Missouri.
The gene replacement therapy designed by Dr. Meyer and her team in collaboration with Elly’s Team is based on an adeno-associated viral (AAV) vector. Production of the plasmid DNA needed to manufacture the vector started just four months following Elly’s diagnosis (in June 2024). The material was provided to Andelyn Biosciences in September, who leveraged their AAV Curator® platform production process and extensive know-how in AAV manufacturing to develop a process and produce clinical material by January 2, 2025.
The speed at which all this work was accomplished reflects the commitment of all involved to get treatment for Elly as quickly as possible. The standard market pace of anywhere from 2 to 10 years for funding, development and commercialization was too much of a risk.
Because of this commitment to beat the clock, Elly was dosed on April 3, 2025, a mere 14 months after her diagnosis and 10 months after their pursuit of gene replacement therapy began. A timeline, according to Michelle, “that was only accomplished due to relentless effort, a lot of prayer, divine intervention and a series of miracles”.
The success of this multifaceted team shows what can be accomplished with grit, determination, and the will to succeed. Michelle also acknowledges that developing this gene replacement therapy treatment for Elly in such a short time was made possible by Michelle and Dan’s network. Those factors enabled them to reach the right people and raise funds to supplement the money and continue to invest into the foundation personally. The Kruegers’ goal is that all patients suffering from this disease will have access to treatment in the future.
The procedure went smoothly, and so far, Elly is doing well. Dan, Michelle, Dr. Grinspan, Dr. Meyer, and everyone at the RTW Foundation, Andelyn Biosciences, and the University of Missouri are anxiously waiting to see how she responds. All are hopeful.
_________
The existence of Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) and the role played by mutations of the IRF2BPL (interferon regulatory factor 2 binding protein-like) gene in the disease were first outlined only in 2018. Much is still not known about the disease.
Although NEDAMSS is a genetic disorder, it is usually not inherited. The IRF2BPL gene is believed to be important for developing and maintaining healthy brain cells. It encodes a protein that is almost exclusively located in the nucleoplasm and acts as a transcriptional regulator.
Mutations of IRF2BPL can be rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel). The different variants can result in different problems, including developmental delays, seizures, movement disorders, and regression of capabilities, all of which can occur to varying degrees depending on the specific mutation. The mutations cause aberrant sequestration of the protein to the cytoplasm, preventing its proper functioning in the nucleus. While symptoms can appear in the first months of life, for most children they appear in early childhood after meeting normal developmental milestones.
Greater understanding of NEDAMSS and its disease pathways has been difficult to obtain due to the very small number of patients so far identified with the condition, the limited information available regarding natural progression of the disease, the lack of direct correlations between different variants and the severity and age of onset of the disease, the lack of neural tissues available for study, no access to well-defined in vitro and animal models, and lack of funding.
Much of the knowledge gained about IRF2BPL mutations linked to NEDAMSS was generated by Dr. Kathrin Meyer and colleagues working at Nationwide Children’s Hospital (NCH). Dr. Meyer is deeply invested in rare disease research and had previously been approached by patient organizations before Elly’s diagnosis to investigate NEDAMSS. She, with the assistance of various collaborators, had performed extensive in vitro studies to characterize disease processes and test potential therapeutic avenues. Initial work with adeno-associated viral (AAV) vectors in patient cells was also performed with preliminary encouraging results. By the time Elly Krueger received her NEDAMSS diagnosis, Dr. Meyer felt strongly that gene replacement therapy was a potential option, but nothing was guaranteed.
Connecting with Dr. Meyer was key to the effort being pursued by Dan and Michelle to develop a treatment for Elly fast enough to make a real difference for their daughter. She was confident that with enough resources they could rapidly and safely produce the gene replacement therapy.
The first step was to avoid the need to raise government funding (a process that can take two years or more and requires extensive pre-existing preclinical data). Thanks to their extensive network, the Kruegers were able to fundraise rapidly with great success. The second key was to perform various aspects of the preclinical work, process development, and manufacturing in parallel rather than sequentially, which further and dramatically shortened the timeline. While helping to reduce the overall development cost, however, this approach introduced real financial risk to the Kruegers and their supporters, as manufacturing began even before the first safety studies or proof of concept studies were started.
Dan and Michelle recognized and accepted the risk, knowing that time was of the essence for Elly. They also were highly focused on moving the project forward. They quickly made decisions based on recommendations provided by various advisors, rather than becoming overwhelmed and involving too many parties with too many differing opinions, which can impede progress.
Preclinical work was completed by the team at NextGen Precision Health, University of Missouri with Dr. Meyers input and oversight. Dr. J Andrea Sierra Delgado moved from NCH to the University of Missouri to join Dr. Saxenas team who was setting up lab space at this new translational institute at that time. It is an incredible achievement of the team to complete the entire project in less than one year despite Dr. Sierra Delgado having to move states to continue the NEDAMSS research.
Proof-of-concept studies were performed with Elly’s cells, and mice, while the company Unravel Biosciences simultaneously performed experiments in tadpoles. Because a well-characterized mouse model of the disease was not available, the researchers used AAV to induce a disease state in healthy mice and treated some of them with the gene replacement therapy. While those that did not receive the treatment experienced loss of physical functionality, the mice treated remained healthy.
In addition to running proof-of-concept and safety studies in parallel, Elly’s Team also made the decision to use pigs rather than rats or monkeys for the large-animal study. Pigs have been shown to reproduce the targeting of the gene replacement therapy virus used in this project and are a good large animal model to facilitate dose-escalation and establish safety in an animal more closely related to humans. They are also easier to handle and faster to breed. Furthermore, for this study, the team used the clinical grade Good Manufacturing Practice (GMP)-compliant material to ensure the results were obtained using the same product that would be used to dose Elly, a decision that was once again made for speed without sacrificing safety. Using valuable clinical material avoided any possibility of needing to perform additional extrapolation studies if there were differences in the research and cGMP batches, which could have significantly delayed Elly’s dosing.
The gene replacement therapy is based on an AAV9 vector designed with elements commonly found in other gene therapies already shown to be safe in clinical applications. AAV9 vectors are widely used for the treatment of genetic neurodegenerative diseases because they travel to brain tissue when injected through blood or spinal fluid. The vector developed to treat NEDAMSS patients delivers a healthy IRF2BPL copy that results in production of a healthy IRF2BPL protein to increase the amount of healthy protein in the nucleoplasm where it can function correctly.
One of the factors making gene replacement therapy attractive for NEDAMSS, according to Dr. Meyer, is the fact that most patients produce small amounts of normal protein. Thus, when the body begins producing the protein that is introduced with the therapy, the immune system does not recognize it as a foreign substance, reducing the likelihood of undesired immune responses—a complication observed with some other gene therapies.
The clinical material was produced at Andelyn Biosciences. Dr. Meyer has worked with Andelyn on many clinical programs over the years and sees the company as a trustworthy resource that reliably provides safe, effective material at speed. In this case, the clinical grade (GMP) gene replacement therapy for Elly was produced and fully released for use in early January 2025. However, to gain more time, Dr. Meyer requested Andelyn to release the material earlier, so it could be tested “at risk” in line with the University of Missouri. This allowed animal studies to commence and be performed in parallel to final release testing. The large-animal safety studies were immediately initiated, and once the data was available, an investigational new drug (IND) application for dosing of Elly with the gene replacement therapy candidate was submitted to the FDA on February 17th.
One important decision made by the entire team regarded the way the new gene replacement therapy would be administered. With neurodegenerative diseases, it is essential that the gene replacement therapy be delivered to and stay in the brain. An effective way to achieve this goal is to inject the therapy into the cerebrospinal fluid surrounding the brain and spinal cord via a method known as Intracisterna Magna injection (ICM). Working with Weill Cornell, this protocol was established as the best-case scenario for the delivery of Elly’s gene replacement therapy.
Carrying this forward, modeling work was done by Dr. Meyer’s to identify the best formulation and safety approach to make this type of delivery possible. In addition to animal and cellular studies, her team at Alcyone Therapeutics used the proprietary FalconTM Precision Delivery Platform to optimize drug delivery parameters for Elly. The team generated a so called “digital twin” – an MRI based computer model of Elly’s brain to help optimize the injection parameters with the goal to allow more drug to spread efficiently around the brain instead of leaking into the peripheral organs.
The IND-application was approved following the 30-day review period of the FDA, and Elly was dosed 14 months from her diagnosis at Weil Cornell Hospital on April 3, 2025. The willingness of the hospital administration to support the Kruegers’ efforts to treat Elly with an experimental gene replacement therapy is an important aspect of this story that cannot be dismissed. Similarly, the open-minded approach to Elly’s treatment taken by her pediatric neurologist Dr. Zachary Grinspan is another.
Now the family and the extended team involved in bringing this new gene replacement therapy to Elly are trying to manage expectations while hoping for the best. There is still a great deal yet unknown about the disease, how the gene replacement therapy is distributed in the brain, whether there will be immune issues, or specifically in Elly’s case, how many brain cells exist that can still respond to treatment. Knowing that some degeneration has already occurred, the hope is the gene replacement therapy will at least slow down and ideally halt progression of the disease.
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Of the many important decisions Michelle and Dan Krueger had to make when pursuing the development and production of a novel gene replacement therapy for Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) was choosing the right contract development and manufacturing organization (CDMO) to manufacture the therapy.
After learning their 8-month-old daughter Elly suffered from a severe form of this ultra-rare neurodegenerative disease, the parents sought out Dr. Kathrin Meyer of Alcyone Therapeutics for her unique knowledge about the cause of NEDAMSS (mutations in the IRF2BPL, or interferon regulatory factor 2 binding protein-like, gene). She encouraged the Kruegers to explore different options and select the CMDO they felt would best meet their needs; there was quite a bit of competition.
Andelyn Biosciences was one of the first CDMOs the Kruegers considered due to the long-term relationship Dr. Meyer has with the company from her time working for Nationwide Children’s Hospital (NCH), from where Andelyn spun out of in 2020. Andelyn was initially formed to produce clinical trial material for physicians conducting gene therapy trials at NCH and today supports many global programs from early to late-stage development and commercial manufacturing.
According to CEO, Wade Macedone, the Andelyn team has much experience working on small projects and does not prioritize Big Pharma clients over emerging biotechs or foundations. In fact, the CDMO reserves a certain percentage of its capacity specifically to support nonprofits, including those involving a single patient and families seeking to access gene therapies for their children.
Mr. Macedone knows that it is not easy for parents like Dan and Michelle to trust an organization they do not know with the production of a novel treatment that will be administered to their child. During his first meeting with Michelle, therefore, he spent time sharing important questions that she should ask of different CDMO contenders, particularly regarding their experience in producing viral vectors used in clinical studies and working with parents focused on saving their children. The latter experience is important because interacting with parents with a severely ill child requires very different skills than those needed when dealing with drug developers.
Dan and Michelle ultimately chose Andelyn Biosciences, largely driven by their expertise, network, and technology. The Andelyn AAV Curator® platform for production of adeno-associated viral (AAV) vectors has been continuously curated over more than 15 years. This adherent platform includes a well-established cell line, well-understood upstream manufacturing and downstream purification processes, and proprietary fit-for-purpose analytical methods for process development and product release. The platform is also available for suspension processes as needed based on afflicted population and dosing required.
Andelyn's data-driven approach to process development leverages decades of production data to shorten timelines while still ensuring cost-effective and improved manufacturing processes. The Curator® platform is also highly predictable in terms of yield and quality and eliminates intellectual property concerns because the technology has all been developed internally. Furthermore, review of investigational new drug (IND) applications is streamlined as the referenced Drug Master Files (DMFs) have been reviewed and approved by the FDA previously, removing unnecessary hurdles and delays.
Another important enabler for the accelerated manufacturing of Elly’s gene replacement therapy was the willingness of Michelle and Dan to rely on Andelyn’s expertise, not disrupt progress with any preconceived ideas of what or how things should be done and listen to guidance regarding what they could do to help—and then follow through.
Effective collaboration and coordination with other service providers also made a difference in so rapidly developing a process and producing the gene replacement therapy for Elly. The DNA plasmids, which are critical raw materials for AAV vector production, were rapidly manufactured while Genezen quickly established a stability and compatibility study to ensure the manufactured clinical product was compatible with the materials of intended injection tools.
Collaboration was particularly crucial to successfully getting the plasmids to Andelyn. They were manufactured at an overseas site and were held up at customs when shipped to the United States. The Kruegers worked closely with Andelyn to get them released indicating, “The team moved mountains for us in getting the plasmids released to not miss our manufacturing start date. This was one of the first mountains Andelyn moved for us in our process, with many more to come”.
Providing rapid and cost-effective gene therapy manufacturing services is not the only way Andelyn is committed to helping families like the Kruegers. In addition to educating parents like Dan and Michelle about critical considerations when selecting a contract manufacturer, Andelyn also seeks to raise awareness and funds for the gene therapy and rare disease community. Many families face not only limited treatment options but lack access to necessary financial and other resources.
Andelyn hosts events like the annual FORE One Purpose golf tournament, the first of which was held in September 2024. When planning for this signature event, Mr. Macedone was seeking a family that could benefit from Andelyn Biosciences’ expertise and capabilities to serve as a great example of what courage, fortitude, and commitment can achieve. The Krueger family was the perfect fit. The $50,000 raised from the first tournament went to Elly’s Team, the foundation established by Michelle and Dan to support development of a cure for NEDAMSS. Planning is well underway for the 2025 event, which will take place on August 11th, 2025.
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A clinical-grade gene replacement therapy being developed, manufactured, and approved for treatment of Elly Krueger in just 10 months is nothing less than amazing.
Much of the success can be attributed to Dan and Michelle, who were constantly managing and coordinating the efforts of the many groups involved in getting treatment for Elly in time to make a difference. The Kruegers also recognize the roles played by all of those groups and many individuals who were so committed to Elly’s cause.
They are extremely grateful that Dr. Zachary Grinspan was on call on Thanksgiving of 2023. His neurological expertise, knowledge of gene therapy, and support for the Kruegers’ efforts to develop a treatment were immensely important. The initial evidence of Dr. Kathrin Meyers’ team showing that gene replacement therapy could potentially help Elly, coupled with her encouragement and network of resources, were also invaluable. The incredible dedication of the team at the University of Missouri to complete proof of concept and safety studies in an extremely fast timeline, and the willingness of the folks at Andelyn Biosciences to take calls at any time of day, enabled filing of the investigational new drug (IND) application with the Food and Drug Administration to proceed smoothly.
That so many different people and organizations were necessary to turn the concept of a gene replacement therapy for NEDAMSS into a reality highlights the complexity that families facing such a devastating diagnosis must overcome.
The Kruegers’ experience also clearly shows that when there is a will, there is a way, to accomplish what many in the industry profess to be impossible. Indeed, it does not have to take 5+ years and $5 million or more to develop every gene therapy. Finding access to a great team, being able to tell your story while illustrating grit and willingness to fight for your son or daughter, and knowledge of safe and effective strategies for accelerating preclinical studies and process development demonstrate that treatments can be made available in much less time and at much lower cost.
In 2024, the Kruegers participated in a charity event called Fore One Purpose, which featured Elly as the Impact Champion. The event raised more than $50,000 towards helping children with ultra rare IRF2BPL diseases and will take place again in August of 2025.
As the Kruegers and their extended team of supporters continue to observe Elly and eagerly wait to hear more about how she is responding to the gene replacement therapy, they are also making plans to continue efforts in support of others in the rare- and ultra-rare disease community.
Michelle and Dan issued a letter to the IRF2BPL community on their website in early May, introducing themselves and Elly’s Team and explaining the work they have done and how it was funded. They hosted a webinar, with Dr. Meyer and Dr. Grinspan, for the families in the community to further explain their path to treatment and the next steps. The manufacturing process developed by Andelyn Biosciences provided more than just the one dose needed to treat Elly. The Kruegers plan to expand the IND and clinical trial to treat more patients, but require continued fundraising to achieve this.
Dan and Michelle do not intend to stop there. Hundreds of thousands of children suffer from rare and ultra-rare neurodegenerative/neurodevelopmental and seizure-based diseases for which there currently are no treatments. They want to apply the experience they have gained developing the NEDAMSS gene replacement therapy for Elly—and the approach used to dramatically shorten the timeline for translating research into treatments—to helping these children and their families.
Having faced the devastating news of their daughter’s diagnosis and fought through the despair it engendered, Michelle and Dan have committed to continuing the fight not just for Elly, but for other parents that are not able to take this kind of action. “For those who have been given much, much is expected. Our despair has been replaced with a deep sense of purpose”, they say. They want to know that when families in the future receive an ultra-rare neurodegenerative disease diagnosis, such as NEDAMSS, they won’t have to hear that there is no cure and accept that as the final answer. They can fight for a path to treatment for their children.
Information about the gene therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.
The Orphan Drug Act defines rare diseases as those that affect less than 200,000 people in the United States. The European Union definition is slightly different, with diseases that affect no more than 1 in 2,000 people considered rare. Those numbers are difficult enough to comprehend, but there are also ultra-rare diseases that affect just 100 to 200 people—or fewer—worldwide. Unfortunately, many young children are experiencing rapid disease progression and limited time and opportunity to receive treatment.
The development of a new drug typically takes many years and billions of dollars. How, then, can parents receiving devastating diagnoses for their children have any chance of finding treatment in time? This blog series outlines the story of one family’s journey from diagnosis to administration of a novel gene replacement therapy 14 months later, and how they were supported by clinicians, researchers, hospitals, universities, and manufacturing organizations to make the seemingly impossible happen for their daughter.
The Krueger family’s journey of gene replacement therapy development began the day before Thanksgiving in 2023. They took 5-month-old Elly, their third child, to the pediatrician to investigate rapid onset of developmental delays, which included strange eye movements almost like her eyes were moving in her head. The evening was spent in the emergency room of Weill Cornell hospital with Elly undergoing every test imaginable, including a CAT scan and magnetic resonance imaging of her brain, an EKG, and visits from an ophthalmologist and neurologist. Everything appeared normal. After leaving a message for Dr. Zachary Grinspan, the lead on-call pediatric neurologist they went home around 3 AM expecting to return after the holiday weekend.
It was the first miracle for the Kruegers, according to Michelle, that Dr. Grinspan, a leading neurologist, was on call that day. He took time Thanksgiving afternoon to not only reach out, but after observing Elly’s eye movements via a video call, meet the family at the hospital for additional testing. He quickly determined she was experiencing focal seizures and infantile spasms and immediately began treating Elly with anti-seizure medications.
While the focal seizures quickly dissipated, the infantile spasms did not. They can randomly develop, resulting from structural issues such as brain tumors, or be due to a genetic disease. After several lines of treatment with no progress, it was clear Elly was suffering from something serious. Further imaging of her brain revealed no structural issues, and the diagnosis was discovered after full genome sequencing: Elly has a genetic mutation in the IRF2BPL gene, which causes Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS).
Dr. Grinspan immediately spent time researching the mutation and informed the Krueger’s an hour later that the mutation was ultra-rare, likely neurodegenerative, and there were no treatments or cure. The Kruegers’ immediate response was, instead of buckling under the devastating news, to fight to develop one.
They founded Elly’s Team, a faith-based foundation with a singular focus on translating medical research into treatment in record time and sought help from numerous quarters. The mother of a son with a different rare disease (who Michelle connected to through a friend of a friend) spent three hours teaching Michelle everything she knew about basic genetics, gene editing, gene replacement therapy, and drug repurposing. Networking also led Michelle and Dan to Rod and Marti at the RTW Foundation, which funds rare disease research, medical innovation, and local community collaborations. A connection that would be invaluable as the Krueger’s continued their journey, with the addition of Joe Katakowski (PhD, Director of Research) to their board, another miracle along the way.
The Kruegers also discovered Dr. Kathrin Meyer, who had miraculously already been working with funding for diseases in the IRF2BPL community. In her role as Chief Scientific Officer of Alcyone Therapeutics, and formally at Nationwide Childrens Hospital, Dr. Meyer was investigating possible treatment avenues for NEDAMSS as part of her research in mutations of the IRF2BPL genes. She, Dr. Grinspan, and experts at the RTW Foundation helped Michelle and Dan to ultimately prioritize three treatment options to pursue: drug repurposing, antisense oligonucleotides (ASOs) to target mRNA or gene addition therapy.
They first reached out to numerous biotech labs and drug developers regarding development of an ASO drug. The IRF2BPL gene presents unique challenges, including that it is a single-exon gene containing no introns and has many repeated sequences (GC-rich in particular), both of which make ASO development difficult. La Jolla Labs, experts in the design of RNA therapeutics, took on the project and after completing an in-depth project, unfortunately confirmed that this approach was not feasible.
In parallel, Michelle and Dan engaged with Unravel Biosciences, which used Elly’s RNA data to identify potential existing drugs that might alter her disease progression. From the list of generated candidates, five lead drugs were selected and are currently being evaluated in a disease-induced tadpole model.
The need became increasingly urgent as the Krueger’s learned over the first few months following Elly’s diagnosis that she fell into the group of children with a severe form of the disease, with progressive debilitation often leading to premature death. The severity of Elly’s disease was unfortunately further confirmed through a repeat MRI in June 2024 indicating brain development challenges and zero percentile head size. Despite many people telling Dan and Michelle that developing a gene replacement therapy would take at least three to five years and $5 to 10 million, they forged ahead with support from Dr. Meyer and Dr. Grinspan, who understood the importance of speed and the need to find a way to go years faster and cheaper without sacrificing safety or efficacy.
The solution was to start developing a clinical manufacturing process at the same time that preclinical (proof-of-concept and safety) studies were being performed. While such an approach was financially risky, it would allow production of clinical material in the least amount of time possible and make it possible to administer the gene replacement therapy to Elly as soon as FDA approval was received.
The preclinical work, including proof of concept and safety studies, was performed at the University of Missouri under the auspices of Dr. J Andrea Sierra Delgado, a colleague of Dr. Meyer’s when they worked together at Nationwide Children’s Hospital and Dr. Smita Saxena, a world-renown neuroscientist and cellular assay specialist. First, the gene replacement therapy was shown to recover Elly’s patient-derived cells. Next, with no mouse model for the disease, Dr. Sierra Delgado and Dr. Saxena confirmed these results in disease-induced wild-type mice, while the team from Unravel confirmed efficacy in mutated tadpoles simultaneously. Safety studies to support an investigational new drug (IND) application were performed in healthy mice and pigs at the University of Missouri.
The gene replacement therapy designed by Dr. Meyer and her team in collaboration with Elly’s Team is based on an adeno-associated viral (AAV) vector. Production of the plasmid DNA needed to manufacture the vector started just four months following Elly’s diagnosis (in June 2024). The material was provided to Andelyn Biosciences in September, who leveraged their AAV Curator® platform production process and extensive know-how in AAV manufacturing to develop a process and produce clinical material by January 2, 2025.
The speed at which all this work was accomplished reflects the commitment of all involved to get treatment for Elly as quickly as possible. The standard market pace of anywhere from 2 to 10 years for funding, development and commercialization was too much of a risk.
Because of this commitment to beat the clock, Elly was dosed on April 3, 2025, a mere 14 months after her diagnosis and 10 months after their pursuit of gene replacement therapy began. A timeline, according to Michelle, “that was only accomplished due to relentless effort, a lot of prayer, divine intervention and a series of miracles”.
The success of this multifaceted team shows what can be accomplished with grit, determination, and the will to succeed. Michelle also acknowledges that developing this gene replacement therapy treatment for Elly in such a short time was made possible by Michelle and Dan’s network. Those factors enabled them to reach the right people and raise funds to supplement the money and continue to invest into the foundation personally. The Kruegers’ goal is that all patients suffering from this disease will have access to treatment in the future.
The procedure went smoothly, and so far, Elly is doing well. Dan, Michelle, Dr. Grinspan, Dr. Meyer, and everyone at the RTW Foundation, Andelyn Biosciences, and the University of Missouri are anxiously waiting to see how she responds. All are hopeful.
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The existence of Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) and the role played by mutations of the IRF2BPL (interferon regulatory factor 2 binding protein-like) gene in the disease were first outlined only in 2018. Much is still not known about the disease.
Although NEDAMSS is a genetic disorder, it is usually not inherited. The IRF2BPL gene is believed to be important for developing and maintaining healthy brain cells. It encodes a protein that is almost exclusively located in the nucleoplasm and acts as a transcriptional regulator.
Mutations of IRF2BPL can be rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel). The different variants can result in different problems, including developmental delays, seizures, movement disorders, and regression of capabilities, all of which can occur to varying degrees depending on the specific mutation. The mutations cause aberrant sequestration of the protein to the cytoplasm, preventing its proper functioning in the nucleus. While symptoms can appear in the first months of life, for most children they appear in early childhood after meeting normal developmental milestones.
Greater understanding of NEDAMSS and its disease pathways has been difficult to obtain due to the very small number of patients so far identified with the condition, the limited information available regarding natural progression of the disease, the lack of direct correlations between different variants and the severity and age of onset of the disease, the lack of neural tissues available for study, no access to well-defined in vitro and animal models, and lack of funding.
Much of the knowledge gained about IRF2BPL mutations linked to NEDAMSS was generated by Dr. Kathrin Meyer and colleagues working at Nationwide Children’s Hospital (NCH). Dr. Meyer is deeply invested in rare disease research and had previously been approached by patient organizations before Elly’s diagnosis to investigate NEDAMSS. She, with the assistance of various collaborators, had performed extensive in vitro studies to characterize disease processes and test potential therapeutic avenues. Initial work with adeno-associated viral (AAV) vectors in patient cells was also performed with preliminary encouraging results. By the time Elly Krueger received her NEDAMSS diagnosis, Dr. Meyer felt strongly that gene replacement therapy was a potential option, but nothing was guaranteed.
Connecting with Dr. Meyer was key to the effort being pursued by Dan and Michelle to develop a treatment for Elly fast enough to make a real difference for their daughter. She was confident that with enough resources they could rapidly and safely produce the gene replacement therapy.
The first step was to avoid the need to raise government funding (a process that can take two years or more and requires extensive pre-existing preclinical data). Thanks to their extensive network, the Kruegers were able to fundraise rapidly with great success. The second key was to perform various aspects of the preclinical work, process development, and manufacturing in parallel rather than sequentially, which further and dramatically shortened the timeline. While helping to reduce the overall development cost, however, this approach introduced real financial risk to the Kruegers and their supporters, as manufacturing began even before the first safety studies or proof of concept studies were started.
Dan and Michelle recognized and accepted the risk, knowing that time was of the essence for Elly. They also were highly focused on moving the project forward. They quickly made decisions based on recommendations provided by various advisors, rather than becoming overwhelmed and involving too many parties with too many differing opinions, which can impede progress.
Preclinical work was completed by the team at NextGen Precision Health, University of Missouri with Dr. Meyers input and oversight. Dr. J Andrea Sierra Delgado moved from NCH to the University of Missouri to join Dr. Saxenas team who was setting up lab space at this new translational institute at that time. It is an incredible achievement of the team to complete the entire project in less than one year despite Dr. Sierra Delgado having to move states to continue the NEDAMSS research.
Proof-of-concept studies were performed with Elly’s cells, and mice, while the company Unravel Biosciences simultaneously performed experiments in tadpoles. Because a well-characterized mouse model of the disease was not available, the researchers used AAV to induce a disease state in healthy mice and treated some of them with the gene replacement therapy. While those that did not receive the treatment experienced loss of physical functionality, the mice treated remained healthy.
In addition to running proof-of-concept and safety studies in parallel, Elly’s Team also made the decision to use pigs rather than rats or monkeys for the large-animal study. Pigs have been shown to reproduce the targeting of the gene replacement therapy virus used in this project and are a good large animal model to facilitate dose-escalation and establish safety in an animal more closely related to humans. They are also easier to handle and faster to breed. Furthermore, for this study, the team used the clinical grade Good Manufacturing Practice (GMP)-compliant material to ensure the results were obtained using the same product that would be used to dose Elly, a decision that was once again made for speed without sacrificing safety. Using valuable clinical material avoided any possibility of needing to perform additional extrapolation studies if there were differences in the research and cGMP batches, which could have significantly delayed Elly’s dosing.
The gene replacement therapy is based on an AAV9 vector designed with elements commonly found in other gene therapies already shown to be safe in clinical applications. AAV9 vectors are widely used for the treatment of genetic neurodegenerative diseases because they travel to brain tissue when injected through blood or spinal fluid. The vector developed to treat NEDAMSS patients delivers a healthy IRF2BPL copy that results in production of a healthy IRF2BPL protein to increase the amount of healthy protein in the nucleoplasm where it can function correctly.
One of the factors making gene replacement therapy attractive for NEDAMSS, according to Dr. Meyer, is the fact that most patients produce small amounts of normal protein. Thus, when the body begins producing the protein that is introduced with the therapy, the immune system does not recognize it as a foreign substance, reducing the likelihood of undesired immune responses—a complication observed with some other gene therapies.
The clinical material was produced at Andelyn Biosciences. Dr. Meyer has worked with Andelyn on many clinical programs over the years and sees the company as a trustworthy resource that reliably provides safe, effective material at speed. In this case, the clinical grade (GMP) gene replacement therapy for Elly was produced and fully released for use in early January 2025. However, to gain more time, Dr. Meyer requested Andelyn to release the material earlier, so it could be tested “at risk” in line with the University of Missouri. This allowed animal studies to commence and be performed in parallel to final release testing. The large-animal safety studies were immediately initiated, and once the data was available, an investigational new drug (IND) application for dosing of Elly with the gene replacement therapy candidate was submitted to the FDA on February 17th.
One important decision made by the entire team regarded the way the new gene replacement therapy would be administered. With neurodegenerative diseases, it is essential that the gene replacement therapy be delivered to and stay in the brain. An effective way to achieve this goal is to inject the therapy into the cerebrospinal fluid surrounding the brain and spinal cord via a method known as Intracisterna Magna injection (ICM). Working with Weill Cornell, this protocol was established as the best-case scenario for the delivery of Elly’s gene replacement therapy.
Carrying this forward, modeling work was done by Dr. Meyer’s to identify the best formulation and safety approach to make this type of delivery possible. In addition to animal and cellular studies, her team at Alcyone Therapeutics used the proprietary FalconTM Precision Delivery Platform to optimize drug delivery parameters for Elly. The team generated a so called “digital twin” – an MRI based computer model of Elly’s brain to help optimize the injection parameters with the goal to allow more drug to spread efficiently around the brain instead of leaking into the peripheral organs.
The IND-application was approved following the 30-day review period of the FDA, and Elly was dosed 14 months from her diagnosis at Weil Cornell Hospital on April 3, 2025. The willingness of the hospital administration to support the Kruegers’ efforts to treat Elly with an experimental gene replacement therapy is an important aspect of this story that cannot be dismissed. Similarly, the open-minded approach to Elly’s treatment taken by her pediatric neurologist Dr. Zachary Grinspan is another.
Now the family and the extended team involved in bringing this new gene replacement therapy to Elly are trying to manage expectations while hoping for the best. There is still a great deal yet unknown about the disease, how the gene replacement therapy is distributed in the brain, whether there will be immune issues, or specifically in Elly’s case, how many brain cells exist that can still respond to treatment. Knowing that some degeneration has already occurred, the hope is the gene replacement therapy will at least slow down and ideally halt progression of the disease.
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Of the many important decisions Michelle and Dan Krueger had to make when pursuing the development and production of a novel gene replacement therapy for Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) was choosing the right contract development and manufacturing organization (CDMO) to manufacture the therapy.
After learning their 8-month-old daughter Elly suffered from a severe form of this ultra-rare neurodegenerative disease, the parents sought out Dr. Kathrin Meyer of Alcyone Therapeutics for her unique knowledge about the cause of NEDAMSS (mutations in the IRF2BPL, or interferon regulatory factor 2 binding protein-like, gene). She encouraged the Kruegers to explore different options and select the CMDO they felt would best meet their needs; there was quite a bit of competition.
Andelyn Biosciences was one of the first CDMOs the Kruegers considered due to the long-term relationship Dr. Meyer has with the company from her time working for Nationwide Children’s Hospital (NCH), from where Andelyn spun out of in 2020. Andelyn was initially formed to produce clinical trial material for physicians conducting gene therapy trials at NCH and today supports many global programs from early to late-stage development and commercial manufacturing.
According to CEO, Wade Macedone, the Andelyn team has much experience working on small projects and does not prioritize Big Pharma clients over emerging biotechs or foundations. In fact, the CDMO reserves a certain percentage of its capacity specifically to support nonprofits, including those involving a single patient and families seeking to access gene therapies for their children.
Mr. Macedone knows that it is not easy for parents like Dan and Michelle to trust an organization they do not know with the production of a novel treatment that will be administered to their child. During his first meeting with Michelle, therefore, he spent time sharing important questions that she should ask of different CDMO contenders, particularly regarding their experience in producing viral vectors used in clinical studies and working with parents focused on saving their children. The latter experience is important because interacting with parents with a severely ill child requires very different skills than those needed when dealing with drug developers.
Dan and Michelle ultimately chose Andelyn Biosciences, largely driven by their expertise, network, and technology. The Andelyn AAV Curator® platform for production of adeno-associated viral (AAV) vectors has been continuously curated over more than 15 years. This adherent platform includes a well-established cell line, well-understood upstream manufacturing and downstream purification processes, and proprietary fit-for-purpose analytical methods for process development and product release. The platform is also available for suspension processes as needed based on afflicted population and dosing required.
Andelyn's data-driven approach to process development leverages decades of production data to shorten timelines while still ensuring cost-effective and improved manufacturing processes. The Curator® platform is also highly predictable in terms of yield and quality and eliminates intellectual property concerns because the technology has all been developed internally. Furthermore, review of investigational new drug (IND) applications is streamlined as the referenced Drug Master Files (DMFs) have been reviewed and approved by the FDA previously, removing unnecessary hurdles and delays.
Another important enabler for the accelerated manufacturing of Elly’s gene replacement therapy was the willingness of Michelle and Dan to rely on Andelyn’s expertise, not disrupt progress with any preconceived ideas of what or how things should be done and listen to guidance regarding what they could do to help—and then follow through.
Effective collaboration and coordination with other service providers also made a difference in so rapidly developing a process and producing the gene replacement therapy for Elly. The DNA plasmids, which are critical raw materials for AAV vector production, were rapidly manufactured while Genezen quickly established a stability and compatibility study to ensure the manufactured clinical product was compatible with the materials of intended injection tools.
Collaboration was particularly crucial to successfully getting the plasmids to Andelyn. They were manufactured at an overseas site and were held up at customs when shipped to the United States. The Kruegers worked closely with Andelyn to get them released indicating, “The team moved mountains for us in getting the plasmids released to not miss our manufacturing start date. This was one of the first mountains Andelyn moved for us in our process, with many more to come”.
Providing rapid and cost-effective gene therapy manufacturing services is not the only way Andelyn is committed to helping families like the Kruegers. In addition to educating parents like Dan and Michelle about critical considerations when selecting a contract manufacturer, Andelyn also seeks to raise awareness and funds for the gene therapy and rare disease community. Many families face not only limited treatment options but lack access to necessary financial and other resources.
Andelyn hosts events like the annual FORE One Purpose golf tournament, the first of which was held in September 2024. When planning for this signature event, Mr. Macedone was seeking a family that could benefit from Andelyn Biosciences’ expertise and capabilities to serve as a great example of what courage, fortitude, and commitment can achieve. The Krueger family was the perfect fit. The $50,000 raised from the first tournament went to Elly’s Team, the foundation established by Michelle and Dan to support development of a cure for NEDAMSS. Planning is well underway for the 2025 event, which will take place on August 11th, 2025.
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A clinical-grade gene replacement therapy being developed, manufactured, and approved for treatment of Elly Krueger in just 10 months is nothing less than amazing.
Much of the success can be attributed to Dan and Michelle, who were constantly managing and coordinating the efforts of the many groups involved in getting treatment for Elly in time to make a difference. The Kruegers also recognize the roles played by all of those groups and many individuals who were so committed to Elly’s cause.
They are extremely grateful that Dr. Zachary Grinspan was on call on Thanksgiving of 2023. His neurological expertise, knowledge of gene therapy, and support for the Kruegers’ efforts to develop a treatment were immensely important. The initial evidence of Dr. Kathrin Meyers’ team showing that gene replacement therapy could potentially help Elly, coupled with her encouragement and network of resources, were also invaluable. The incredible dedication of the team at the University of Missouri to complete proof of concept and safety studies in an extremely fast timeline, and the willingness of the folks at Andelyn Biosciences to take calls at any time of day, enabled filing of the investigational new drug (IND) application with the Food and Drug Administration to proceed smoothly.
That so many different people and organizations were necessary to turn the concept of a gene replacement therapy for NEDAMSS into a reality highlights the complexity that families facing such a devastating diagnosis must overcome.
The Kruegers’ experience also clearly shows that when there is a will, there is a way, to accomplish what many in the industry profess to be impossible. Indeed, it does not have to take 5+ years and $5 million or more to develop every gene therapy. Finding access to a great team, being able to tell your story while illustrating grit and willingness to fight for your son or daughter, and knowledge of safe and effective strategies for accelerating preclinical studies and process development demonstrate that treatments can be made available in much less time and at much lower cost.
In 2024, the Kruegers participated in a charity event called Fore One Purpose, which featured Elly as the Impact Champion. The event raised more than $50,000 towards helping children with ultra rare IRF2BPL diseases and will take place again in August of 2025.
As the Kruegers and their extended team of supporters continue to observe Elly and eagerly wait to hear more about how she is responding to the gene replacement therapy, they are also making plans to continue efforts in support of others in the rare- and ultra-rare disease community.
Michelle and Dan issued a letter to the IRF2BPL community on their website in early May, introducing themselves and Elly’s Team and explaining the work they have done and how it was funded. They hosted a webinar, with Dr. Meyer and Dr. Grinspan, for the families in the community to further explain their path to treatment and the next steps. The manufacturing process developed by Andelyn Biosciences provided more than just the one dose needed to treat Elly. The Kruegers plan to expand the IND and clinical trial to treat more patients, but require continued fundraising to achieve this.
Dan and Michelle do not intend to stop there. Hundreds of thousands of children suffer from rare and ultra-rare neurodegenerative/neurodevelopmental and seizure-based diseases for which there currently are no treatments. They want to apply the experience they have gained developing the NEDAMSS gene replacement therapy for Elly—and the approach used to dramatically shorten the timeline for translating research into treatments—to helping these children and their families.
Having faced the devastating news of their daughter’s diagnosis and fought through the despair it engendered, Michelle and Dan have committed to continuing the fight not just for Elly, but for other parents that are not able to take this kind of action. “For those who have been given much, much is expected. Our despair has been replaced with a deep sense of purpose”, they say. They want to know that when families in the future receive an ultra-rare neurodegenerative disease diagnosis, such as NEDAMSS, they won’t have to hear that there is no cure and accept that as the final answer. They can fight for a path to treatment for their children.
Information about the gene therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.