Accelerating Development of Gene Replacement Therapy to Treat NEDAMSS
One Family’s Journey from Diagnosis to Gene Replacement Therapy in 14 Months: Part TWO
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.
In this series, you can read about one family who refused to take this diagnosis as the end. They managed to bring together the resources and people needed to get an investigational gene replacement therapy manufactured and approved by the Food and Drug Administration (FDA) so that their daughter, Elly Krueger, could be dosed on April 3, 2025, just 14 months from her diagnosis.
In Part ONE, we covered the journey of Michelle and Dan Krueger and their daughter Elly, who was diagnosed with Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS), a recently identified (2018) ultra-rare, progressive, neurodegenerative disease that affects roughly 150 children in the entire world.
Here in Part TWO we will discuss the science of NEDAMSS and highlight the efforts of Dr. Kathrin Meyer, in collaboration with Elly’s Team and a team of researchers, who collectively developed the gene replacement therapy and conducted the preclinical studies necessary for achieving a N=1 drug approval from the FDA. Part THREE will cover the work involved in accelerating the process development and manufacture of the novel gene replacement therapy by Andelyn Biosciences, while Part FOUR will summarize the important roles played by the different parties and looks at the next steps for Elly, her family, the other children, and the Elly’s Team foundation.
Part TWO:
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.
Learn more about keys to accelerating production of Elly’s gene replacement therapy in Part THREE or take a step back to the beginning in Part ONE.
Information about the gene replacement therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/.
For details about the partners in development, please visit https://alcyonetx.com/ or https://research.missouri.edu/news/speeding-scientific-pipeline. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.
One Family’s Journey from Diagnosis to Gene Replacement Therapy in 14 Months: Part TWO
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.
In this series, you can read about one family who refused to take this diagnosis as the end. They managed to bring together the resources and people needed to get an investigational gene replacement therapy manufactured and approved by the Food and Drug Administration (FDA) so that their daughter, Elly Krueger, could be dosed on April 3, 2025, just 14 months from her diagnosis.
In Part ONE, we covered the journey of Michelle and Dan Krueger and their daughter Elly, who was diagnosed with Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS), a recently identified (2018) ultra-rare, progressive, neurodegenerative disease that affects roughly 150 children in the entire world.
Here in Part TWO we will discuss the science of NEDAMSS and highlight the efforts of Dr. Kathrin Meyer, in collaboration with Elly’s Team and a team of researchers, who collectively developed the gene replacement therapy and conducted the preclinical studies necessary for achieving a N=1 drug approval from the FDA. Part THREE will cover the work involved in accelerating the process development and manufacture of the novel gene replacement therapy by Andelyn Biosciences, while Part FOUR will summarize the important roles played by the different parties and looks at the next steps for Elly, her family, the other children, and the Elly’s Team foundation.
Part TWO:
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.
Learn more about keys to accelerating production of Elly’s gene replacement therapy in Part THREE or take a step back to the beginning in Part ONE.
Information about the gene replacement therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/.
For details about the partners in development, please visit https://alcyonetx.com/ or https://research.missouri.edu/news/speeding-scientific-pipeline. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.
One Family’s Journey from Diagnosis to Gene Replacement Therapy in 14 Months: Part TWO
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.
In this series, you can read about one family who refused to take this diagnosis as the end. They managed to bring together the resources and people needed to get an investigational gene replacement therapy manufactured and approved by the Food and Drug Administration (FDA) so that their daughter, Elly Krueger, could be dosed on April 3, 2025, just 14 months from her diagnosis.
In Part ONE, we covered the journey of Michelle and Dan Krueger and their daughter Elly, who was diagnosed with Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS), a recently identified (2018) ultra-rare, progressive, neurodegenerative disease that affects roughly 150 children in the entire world.
Here in Part TWO we will discuss the science of NEDAMSS and highlight the efforts of Dr. Kathrin Meyer, in collaboration with Elly’s Team and a team of researchers, who collectively developed the gene replacement therapy and conducted the preclinical studies necessary for achieving a N=1 drug approval from the FDA. Part THREE will cover the work involved in accelerating the process development and manufacture of the novel gene replacement therapy by Andelyn Biosciences, while Part FOUR will summarize the important roles played by the different parties and looks at the next steps for Elly, her family, the other children, and the Elly’s Team foundation.
Part TWO:
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.
Learn more about keys to accelerating production of Elly’s gene replacement therapy in Part THREE or take a step back to the beginning in Part ONE.
Information about the gene replacement therapy development and manufacturing capabilities at Andelyn Biosciences can be found here: https://www.andelynbio.com/.
For details about the partners in development, please visit https://alcyonetx.com/ or https://research.missouri.edu/news/speeding-scientific-pipeline. And to stay up to date on the work being accomplished by Elly’s Team, visit https://ellysteam.org/.