Genetic Engineering
Delivering Genetic Editing Therapies to Market
In the past 10 years, our understanding of molecular biology and genetic engineering has continued to expand. Breakthrough approaches in genome editing are revolutionizing therapeutic research, with the first CRISPR-based treatment set to apply for regulatory approval by the end of 2022.1.
In this blog, Dr. Rajiv Vaidya, Head of Manufacturing Science & Technology (MS&T), and Dr. Samir Acharya, Associate Director of Process Development, provide their unique insight into the steps necessary to allow commercially available gene therapy treatments to become a reality.
Enhancing Therapies with Gene Editing
There are over 10,000 known human diseases caused by single-gene mutations, and despite being relatively rare, these genetic diseases are thought to affect around 1% of the global population. In the last decade, innovations have enabled the development of genome editing technology capable of inserting, deleting, modifying, or replacing a DNA sequence to overcome the effects of genetic abnormalities. These revolutionary new gene editing technologies include:
CRISPR-Cas
The CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) can be used to specifically target DNA sequences and make a double-stranded DNA strand break. Depending on the CRISPR system being used, the targeted DNA can be inactivated during repair, or the genes can be manipulated to add new DNA segments or edit single nucleotides. The guide RNA directs the Cas9 protein to the precise target sequence, enabling highly specific modifications.
Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs)
Like CRISPR-Cas technologies, ZFNs act to create double-stranded breaks in DNA at specified locations. The zinc finger domains of ZFNs recognize and bind to specific DNA sequences, effectively delivering and directing the nuclease component to the desired cut site. The cell’s natural DNA-repair processes are then stimulated and harnessed to generate precise edits at the target site.
As these molecular tools have advanced, their capabilities have inspired biopharma developers and researchers to broaden their use into various therapeutic areas, from cancers to motor neuron disorders2,3.
Transcription Activator-Like Effector Nucleases (TALENs)
TALENs are another genome editing technology, using transcription activator-like effector proteins to bind specific DNA sequences and induce targeted double-stranded DNA breaks. TALENs allow for precise genome modifications, making them a valuable tool in life sciences and genetic research.
Making Genetic Editing a Reality
Effective editing of human genomes not only relies on the controlled and precise alteration of a DNA sequence by technologies like ZFNs or CRISPR-Cas, but also the delivery of the editing tool to the target cell. Delivery poses its own challenges, requiring
- Protection of the nucleic acid encoding the editing machinery throughout its journey from the administration site to the target
- Specific recognition of target tissues or cell types
- Insertion of the editing machinery genes into target cells
Considering these requirements, gene therapy developers are looking towards viral vectors like adeno-associated virus (AAV) and lentivirus (LV) as potential delivery vehicles. With the ability to carry relatively large cassettes, viral vectors could be used to transport genetic material encoding the gene editing machinery to specific target tissues and cell types. Utilizing certain serotypes and pseudotyping could further help refine the viral vectors’ tropism and enhance target cell specificity. Viral vectors like AAV are also considered to be poorly immunogenic, enabling the protection of genetic cargo from destruction by the host immune system.
Overcoming Challenges on the Path to Commercial Availability
For revolutionary genome editing technologies to change the lives of patients, developers and manufacturers will need to overcome the challenges on the path to clinical trial and commercial production.
Ensuring patient safety
As with all therapies introducing or modifying genetic material within patient cells, safety should be of the utmost importance. Risks stemming from off-target interactions, uncontrolled recombination events, or immunogenicity must be considered and minimized.
Preventing risk will not only require a strong understanding of gene function and activity of gene editing machinery but also the delivery vehicle. A high level of expertise in viral vector development will be needed to carefully design vectors to prevent off-target delivery and immunogenic reactions. Manufacturing processes must be optimized to enhance purity: minimizing the presence of residuals, empty capsids, or contaminants. Extensive analytical expertise will also be critical for purity and safety assessment while demonstrating the absence of potential risks to patient health.
Considering scale
Delivering new therapeutics to market successfully requires scalable manufacturing processes that have been optimized with cost in mind, as higher production prices will limit patient access.
However, building robust processes and analytical methods while working with a relatively new drug modality is challenging. This is compounded by the fact that the production of advanced therapies like genome editing technologies will cost significantly more than conventional biologics such as monoclonal antibodies (mAbs).
By working with contract development and manufacturing organizations (CDMOs) with extensive experience in viral vector manufacturing, drug developers can be assured that processes have been built with consideration to scalability and cost. As a result, critical new therapies can be delivered to a broader patient population faster.
New technologies bring unique challenges
Potentially unfamiliar challenges are likely to arise when working in new areas like genome engineering. The regulatory landscape governing these technologies will initially be dynamic and, as the genome editing space matures, requirements will evolve in tandem. Growing evidence from preclinical and clinical trials, as well as advances in analytical techniques, will act to mold the regulations governing the genome editing space. As a result, developers and manufacturers must demonstrate flexibility while staying abreast of innovations, industry advancements, and evolving regulations.
A Look to the Future
The potential for genome editing to rectify genetic abnormalities in patients’ cells and effectively cure genetic diseases is an attractive prospect that could be within grasp in the not-so-distant future. Realizing this possibility, however, will rely on the effective development and manufacturing of new therapies at scale, likely giving rise to unique challenges. Navigating the difficulties ahead and making gene editing a reality for patients will necessitate manufacturers with proven expertise in areas like viral vector production and analytics.
To find out more about how Andelyn Biosciences can help with your next viral vector project, contact us today.
References
- https://geneticalliance.org.uk/information/learn-about-genetics/genetic-disorders/#:~:text=Single%20gene%20disorders%20are%20caused,mutation%2C%20in%20a%20single%20gene.
- https://www.statnews.com/2022/02/10/drugs-based-on-next-generation-crispr-moving-toward-the-clinic-faster/
- https://clinicaltrials.gov/ct2/results?cond=&term=CRISPR&cntry=&state=&city=&dist=
Delivering Genetic Editing Therapies to Market
In the past 10 years, our understanding of molecular biology and genetic engineering has continued to expand. Breakthrough approaches in genome editing are revolutionizing therapeutic research, with the first CRISPR-based treatment set to apply for regulatory approval by the end of 2022.1.
In this blog, Dr. Rajiv Vaidya, Head of Manufacturing Science & Technology (MS&T), and Dr. Samir Acharya, Associate Director of Process Development, provide their unique insight into the steps necessary to allow commercially available gene therapy treatments to become a reality.
Enhancing Therapies with Gene Editing
There are over 10,000 known human diseases caused by single-gene mutations, and despite being relatively rare, these genetic diseases are thought to affect around 1% of the global population. In the last decade, innovations have enabled the development of genome editing technology capable of inserting, deleting, modifying, or replacing a DNA sequence to overcome the effects of genetic abnormalities. These revolutionary new gene editing technologies include:
CRISPR-Cas
The CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) can be used to specifically target DNA sequences and make a double-stranded DNA strand break. Depending on the CRISPR system being used, the targeted DNA can be inactivated during repair, or the genes can be manipulated to add new DNA segments or edit single nucleotides. The guide RNA directs the Cas9 protein to the precise target sequence, enabling highly specific modifications.
Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs)
Like CRISPR-Cas technologies, ZFNs act to create double-stranded breaks in DNA at specified locations. The zinc finger domains of ZFNs recognize and bind to specific DNA sequences, effectively delivering and directing the nuclease component to the desired cut site. The cell’s natural DNA-repair processes are then stimulated and harnessed to generate precise edits at the target site.
As these molecular tools have advanced, their capabilities have inspired biopharma developers and researchers to broaden their use into various therapeutic areas, from cancers to motor neuron disorders2,3.
Transcription Activator-Like Effector Nucleases (TALENs)
TALENs are another genome editing technology, using transcription activator-like effector proteins to bind specific DNA sequences and induce targeted double-stranded DNA breaks. TALENs allow for precise genome modifications, making them a valuable tool in life sciences and genetic research.
Making Genetic Editing a Reality
Effective editing of human genomes not only relies on the controlled and precise alteration of a DNA sequence by technologies like ZFNs or CRISPR-Cas, but also the delivery of the editing tool to the target cell. Delivery poses its own challenges, requiring
- Protection of the nucleic acid encoding the editing machinery throughout its journey from the administration site to the target
- Specific recognition of target tissues or cell types
- Insertion of the editing machinery genes into target cells
Considering these requirements, gene therapy developers are looking towards viral vectors like adeno-associated virus (AAV) and lentivirus (LV) as potential delivery vehicles. With the ability to carry relatively large cassettes, viral vectors could be used to transport genetic material encoding the gene editing machinery to specific target tissues and cell types. Utilizing certain serotypes and pseudotyping could further help refine the viral vectors’ tropism and enhance target cell specificity. Viral vectors like AAV are also considered to be poorly immunogenic, enabling the protection of genetic cargo from destruction by the host immune system.
Overcoming Challenges on the Path to Commercial Availability
For revolutionary genome editing technologies to change the lives of patients, developers and manufacturers will need to overcome the challenges on the path to clinical trial and commercial production.
Ensuring patient safety
As with all therapies introducing or modifying genetic material within patient cells, safety should be of the utmost importance. Risks stemming from off-target interactions, uncontrolled recombination events, or immunogenicity must be considered and minimized.
Preventing risk will not only require a strong understanding of gene function and activity of gene editing machinery but also the delivery vehicle. A high level of expertise in viral vector development will be needed to carefully design vectors to prevent off-target delivery and immunogenic reactions. Manufacturing processes must be optimized to enhance purity: minimizing the presence of residuals, empty capsids, or contaminants. Extensive analytical expertise will also be critical for purity and safety assessment while demonstrating the absence of potential risks to patient health.
Considering scale
Delivering new therapeutics to market successfully requires scalable manufacturing processes that have been optimized with cost in mind, as higher production prices will limit patient access.
However, building robust processes and analytical methods while working with a relatively new drug modality is challenging. This is compounded by the fact that the production of advanced therapies like genome editing technologies will cost significantly more than conventional biologics such as monoclonal antibodies (mAbs).
By working with contract development and manufacturing organizations (CDMOs) with extensive experience in viral vector manufacturing, drug developers can be assured that processes have been built with consideration to scalability and cost. As a result, critical new therapies can be delivered to a broader patient population faster.
New technologies bring unique challenges
Potentially unfamiliar challenges are likely to arise when working in new areas like genome engineering. The regulatory landscape governing these technologies will initially be dynamic and, as the genome editing space matures, requirements will evolve in tandem. Growing evidence from preclinical and clinical trials, as well as advances in analytical techniques, will act to mold the regulations governing the genome editing space. As a result, developers and manufacturers must demonstrate flexibility while staying abreast of innovations, industry advancements, and evolving regulations.
A Look to the Future
The potential for genome editing to rectify genetic abnormalities in patients’ cells and effectively cure genetic diseases is an attractive prospect that could be within grasp in the not-so-distant future. Realizing this possibility, however, will rely on the effective development and manufacturing of new therapies at scale, likely giving rise to unique challenges. Navigating the difficulties ahead and making gene editing a reality for patients will necessitate manufacturers with proven expertise in areas like viral vector production and analytics.
To find out more about how Andelyn Biosciences can help with your next viral vector project, contact us today.
References
- https://geneticalliance.org.uk/information/learn-about-genetics/genetic-disorders/#:~:text=Single%20gene%20disorders%20are%20caused,mutation%2C%20in%20a%20single%20gene.
- https://www.statnews.com/2022/02/10/drugs-based-on-next-generation-crispr-moving-toward-the-clinic-faster/
- https://clinicaltrials.gov/ct2/results?cond=&term=CRISPR&cntry=&state=&city=&dist=
Delivering Genetic Editing Therapies to Market
In the past 10 years, our understanding of molecular biology and genetic engineering has continued to expand. Breakthrough approaches in genome editing are revolutionizing therapeutic research, with the first CRISPR-based treatment set to apply for regulatory approval by the end of 2022.1.
In this blog, Dr. Rajiv Vaidya, Head of Manufacturing Science & Technology (MS&T), and Dr. Samir Acharya, Associate Director of Process Development, provide their unique insight into the steps necessary to allow commercially available gene therapy treatments to become a reality.
Enhancing Therapies with Gene Editing
There are over 10,000 known human diseases caused by single-gene mutations, and despite being relatively rare, these genetic diseases are thought to affect around 1% of the global population. In the last decade, innovations have enabled the development of genome editing technology capable of inserting, deleting, modifying, or replacing a DNA sequence to overcome the effects of genetic abnormalities. These revolutionary new gene editing technologies include:
CRISPR-Cas
The CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) can be used to specifically target DNA sequences and make a double-stranded DNA strand break. Depending on the CRISPR system being used, the targeted DNA can be inactivated during repair, or the genes can be manipulated to add new DNA segments or edit single nucleotides. The guide RNA directs the Cas9 protein to the precise target sequence, enabling highly specific modifications.
Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs)
Like CRISPR-Cas technologies, ZFNs act to create double-stranded breaks in DNA at specified locations. The zinc finger domains of ZFNs recognize and bind to specific DNA sequences, effectively delivering and directing the nuclease component to the desired cut site. The cell’s natural DNA-repair processes are then stimulated and harnessed to generate precise edits at the target site.
As these molecular tools have advanced, their capabilities have inspired biopharma developers and researchers to broaden their use into various therapeutic areas, from cancers to motor neuron disorders2,3.
Transcription Activator-Like Effector Nucleases (TALENs)
TALENs are another genome editing technology, using transcription activator-like effector proteins to bind specific DNA sequences and induce targeted double-stranded DNA breaks. TALENs allow for precise genome modifications, making them a valuable tool in life sciences and genetic research.
Making Genetic Editing a Reality
Effective editing of human genomes not only relies on the controlled and precise alteration of a DNA sequence by technologies like ZFNs or CRISPR-Cas, but also the delivery of the editing tool to the target cell. Delivery poses its own challenges, requiring
- Protection of the nucleic acid encoding the editing machinery throughout its journey from the administration site to the target
- Specific recognition of target tissues or cell types
- Insertion of the editing machinery genes into target cells
Considering these requirements, gene therapy developers are looking towards viral vectors like adeno-associated virus (AAV) and lentivirus (LV) as potential delivery vehicles. With the ability to carry relatively large cassettes, viral vectors could be used to transport genetic material encoding the gene editing machinery to specific target tissues and cell types. Utilizing certain serotypes and pseudotyping could further help refine the viral vectors’ tropism and enhance target cell specificity. Viral vectors like AAV are also considered to be poorly immunogenic, enabling the protection of genetic cargo from destruction by the host immune system.
Overcoming Challenges on the Path to Commercial Availability
For revolutionary genome editing technologies to change the lives of patients, developers and manufacturers will need to overcome the challenges on the path to clinical trial and commercial production.
Ensuring patient safety
As with all therapies introducing or modifying genetic material within patient cells, safety should be of the utmost importance. Risks stemming from off-target interactions, uncontrolled recombination events, or immunogenicity must be considered and minimized.
Preventing risk will not only require a strong understanding of gene function and activity of gene editing machinery but also the delivery vehicle. A high level of expertise in viral vector development will be needed to carefully design vectors to prevent off-target delivery and immunogenic reactions. Manufacturing processes must be optimized to enhance purity: minimizing the presence of residuals, empty capsids, or contaminants. Extensive analytical expertise will also be critical for purity and safety assessment while demonstrating the absence of potential risks to patient health.
Considering scale
Delivering new therapeutics to market successfully requires scalable manufacturing processes that have been optimized with cost in mind, as higher production prices will limit patient access.
However, building robust processes and analytical methods while working with a relatively new drug modality is challenging. This is compounded by the fact that the production of advanced therapies like genome editing technologies will cost significantly more than conventional biologics such as monoclonal antibodies (mAbs).
By working with contract development and manufacturing organizations (CDMOs) with extensive experience in viral vector manufacturing, drug developers can be assured that processes have been built with consideration to scalability and cost. As a result, critical new therapies can be delivered to a broader patient population faster.
New technologies bring unique challenges
Potentially unfamiliar challenges are likely to arise when working in new areas like genome engineering. The regulatory landscape governing these technologies will initially be dynamic and, as the genome editing space matures, requirements will evolve in tandem. Growing evidence from preclinical and clinical trials, as well as advances in analytical techniques, will act to mold the regulations governing the genome editing space. As a result, developers and manufacturers must demonstrate flexibility while staying abreast of innovations, industry advancements, and evolving regulations.
A Look to the Future
The potential for genome editing to rectify genetic abnormalities in patients’ cells and effectively cure genetic diseases is an attractive prospect that could be within grasp in the not-so-distant future. Realizing this possibility, however, will rely on the effective development and manufacturing of new therapies at scale, likely giving rise to unique challenges. Navigating the difficulties ahead and making gene editing a reality for patients will necessitate manufacturers with proven expertise in areas like viral vector production and analytics.
To find out more about how Andelyn Biosciences can help with your next viral vector project, contact us today.
References
- https://geneticalliance.org.uk/information/learn-about-genetics/genetic-disorders/#:~:text=Single%20gene%20disorders%20are%20caused,mutation%2C%20in%20a%20single%20gene.
- https://www.statnews.com/2022/02/10/drugs-based-on-next-generation-crispr-moving-toward-the-clinic-faster/
- https://clinicaltrials.gov/ct2/results?cond=&term=CRISPR&cntry=&state=&city=&dist=