Gene therapy is promising biotechnology with the potential to treat or cure diseases caused by a mutated gene. By introducing new genetic material into a person’s cells, researchers hope to replace or repair faulty genes so that they can make beneficial proteins instead of toxic ones.
The challenge in gene therapy is finding a way to get new genetic material inside the body and deliver it to human cells. Once researchers realized that viruses have the ability to deposit new DNA into cells, they found a way to harness that power. By removing the viruses’ damaging genetic material from cells and replacing it with new, desired genes, scientists can use viruses as vectors to deposit helpful genetic material.
Adeno-associated virus (AAV) vectors are one of the most promising gene delivery systems for gene therapy.
What is AAV Gene Therapy?
AAV gene therapy refers to the use of adeno-associated virus vectors to deliver new genetic material to human cells. AAVs are seen as an ideal vector for gene therapy because they are small viruses that are not known to cause disease in humans on their own. They’re also capable of infecting various types of cells and can be modified in a way that lets researchers control whether the new genes are incorporated into the host genome.1
AAVs can be used to deliver genetic material that can replace, silence, or edit problematic genes in specific cell types where a disease manifests. For example, research funded in part by Target ALS explored the use of an AAV that is directed to respiratory motor neurons where expression of mutated SOD1 genes can inhibit breathing in patients with ALS.2 The AAV carries a special kind of RNA, called a microRNA (AAV-miRSOD1), that suppresses expression of a gene containing the matching microRNA sequence. The study showed that suppression of mutant SOD1 in respiratory motor neurons prolonged survival and enhanced breathing in the ALS mouse model.2
AAVs are considered the most promising vehicles for delivering in-vivo gene therapies (that is, therapies that are performed inside a living organism). Researchers are continually developing ways to engineer the capsid (or protein shell) of AAVs to perfect new designs that will ensure clinical success.
What Diseases Use AAV Gene Therapy?
AAVs are one of the few types of viruses that can be reliably integrated into the central nervous system (CNS). For that reason, they have become the vector of choice in gene therapies used in Alzheimer’s disease, Canavan’s disease, and Parkinson’s disease.3 There have also been clinical trials in the use of AAV-mediated gene therapies for a number of cancers as well as spinal muscular atrophy, metachromatic leukodystrophy, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).4
While researchers have sought to delay or stop the progression of these neurodegenerative diseases, they have not always been successful. In many cases, this is likely due to our lack of knowledge about the genes involved in the disease expression rather than the shortcomings of AAV gene therapy itself.
Thus far, the crowning achievement of AAV gene therapy has been its successful use in spinal muscular atrophy in young infants.5
AAV Gene Therapy for ALS
In general, ALS has been a challenge for gene therapy researchers because its symptoms have been linked to so many gene mutations, both inherited and non-inherited. Despite this, researchers still lack complete knowledge of specific therapeutic targets that could change the outcome of an ALS diagnosis. Injection sites for AAV gene therapies would ideally be in the brain or spinal cord (for CNS targeting), which poses more significant risks for ALS clinical trial patients.
Despite these difficulties, researchers have greatly expanded their knowledge of ALS genetics in the last decade, making way for ALS gene therapy clinical trials targeting:
- SOD1 mutations
- C9orf72 hexanucleotide repeat expansions
- ATXN2 trinucleotide expansions
- FUS mutations
For example, Target ALS-funded scientists have published studies on the role of mutations in the FUS RNA-binding protein in severe forms of ALS.6 Researchers hope to find a way for an AAV vector to carry a wild-type FUS gene allele in order to decrease the expression of mutant proteins that causes rapid neurodegeneration.
The specifics of AAV vectors, such as the design of capsids and how they affect gene editing and delivery, are also at the center of new and ongoing research that aims to treat ALS. Because the production of AAV biotechnology is costly and time-consuming, Target ALS provides investigators with access to high-quality AAV and tools for target validation alongside Virovek, a contract research organization specializing in recombinant AAV production.
Target ALS has also expanded its Stem Cell Core to include four new reporter lines in order to meet the demand from researchers and to encourage collaboration. Three of these lines involve the insertion of plasmids into a specific AAV viral vector (AAV1). AAV1 has so far been the most efficient vector for targeting various brain regions.
The Advantages of AAV Gene Therapy
AAV vectors have a broad host range, meaning that they can be used in research on multiple organisms before clinical trials on humans begin. However, their main advantages are their lack of immunogenicity and pathogenicity in humans.
AAVs also tend to be efficient in delivering new genetic material (when they are able to reach their location) as well as facilitate the sustained production of new, therapeutic proteins with little resulting toxicity. And with funding from Target ALS, there are more opportunities for collaboration than ever before when it comes to exploring the use of these unique vectors.
These are just some of the reasons AAVs are being explored for use in a wide range of clinical applications.
The Future of AAV Gene Therapy
Despite the advantages of AAV therapy for diseases including ALS, critical challenges remain. AAV vectors have not been successful in reaching every target cell or tissue. While AAVs do not cause disease, they can still stimulate an immune response in the body that interferes with the therapeutic benefits of gene therapy. In diseases like ALS, many of the mechanisms underlying the disease remain unknown. In these cases, researchers don’t have a target for AAV gene therapies.
However, AAV vectors remain our best hope for gene delivery. That’s why Target ALS will continue to support the study of AAVs in a cooperative atmosphere that drives research forward with maximum transparency and lays the groundwork for future clinical success.
Frequently Asked Questions
How many AAV gene therapies are FDA approved?
Thus far, there have been eight AAV gene therapies approved by the Food and Drug Administration. These have fallen under three types of viral vectors including adeno-associated virus, herpes simplex virus, and lentivirus.
Is AAV RNA or DNA?
AAV holds a single-stranded DNA genome belonging to the Parvoviridae family. Infection by AAV happens within the presence of a helper virus which can be either a herpesvirus or adenovirus.
How long does AAV gene therapy work?
Improvements have been shown in patients’ vision who received an ocular AAV gene transfer. They remained stable for 4 years following treatment.
Are AAV vectors safe?
AAV vectors are considered safe as long as dose sizes are monitored.
1. Deyle, D. R., & Russell, D. W. (2009, Aug 11). Adeno-associated virus vector integration. Current Opinion in Molecular Therapeutics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929125/
2. Keeler-Klunk, A. & Zieger, M., et al. (2019, Dec). Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model. Molecular Therapy – Methods & Clinical Development. https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(19)30156-1
3. Weinberg, M. S., Samulski, R. J., & McCown, T. J. (2013, Mar 17). Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887624/
4. Qu, Y., Liu, Y., et al. (2019, Jun 14). Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases. Neural Regeneration Research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404499/
5. Office of the Commissioner. (2019, May 24) FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. U.S. Food and Drug Administration. Retrieved September 29, 2022, from https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease
6. Sanjuan-Ruiz, I., Govea-Perez, N., et al. (2021, Sep 6) Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation. Molecular Neurodegeneration. https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00477-w