Introduction
In some areas of the clinical trials community, it is a common assumption that a gene therapy is always one-and-done. This includes the idea that once a gene therapy has been administered to a person, that person must be ineligible for, or excluded from, any further gene therapy treatments. While it is correct that some gene therapies cannot be readministered to the same person using current technology, there are many important exceptions to this rule, and many potential new approaches on the horizon to enable redosing in the future. This blog post will briefly summarize the current state of gene therapies and some promising future directions.
Gene Therapy Overview
Broadly speaking, a gene therapy treatment is a drug product intended to produce a therapeutic effect by altering genetic content (i.e. deoxyribonucleic acid (DNA) and/or ribonucleic acid (RNA)) within a cell. Viruses are biological agents that have evolved over billions of years to alter the genetic content of cells to enable viral propagation and transmission. Scientists have taken advantage of these viral systems to convert wild viruses into engineered vectors, capable of delivering a therapeutic genetic payload to target cells. For in vivo clinical applications, the most widely used viral vectors are various types of Adeno-Associated Virus (AAV) vectors. Importantly, however, gene therapy products under development, or having FDA marketing approval, use a broad range of other viruses as the basic vector building block.
The basic structure of an AAV vector is an outer layer made up of twenty identical capsid proteins, surrounding a DNA payload of 4,000-5,000 DNA bases, or nucleotides. The twenty capsids fit together into an icosahedron surrounding the DNA core. When an AAV is introduced into the human body, it provokes an immune response, resulting in antibodies capable of binding to the capsid and neutralizing the virus or vector. In the wild, AAVs have been found to use over a dozen different flavors (serotypes) of capsids. There is limited cross-reactivity for human antibodies among the capsid serotypes. For example, approximately 70% of the human population already have antibodies against AAV serotype 2, due to exposure to the wild virus. These persons would be mostly excluded from systemic treatment with a gene therapy vector using AAV2 capsid due to the likely presence of neutralizing antibodies that would block viral delivery. These same persons may be eligible for treatment with a different AAV serotype vector.
For many AAV-based gene therapies, the presence of pre-existing antibodies in a person’s blood against the respective serotype is an exclusion factor, making that person ineligible for treatment. When a seronegative (eligible) person is treated systemically with an AAV vector, it is generally expected that neutralizing antibodies will develop, making that person ineligible for retreatment or redosing with any AAV vector of the same serotype. This is the basis of the idea that gene therapies must always be administered as a one-time treatment, with no option for redosing. As noted, there are a variety of exceptions to this rule.
Table 1
| initial dose | subsequent dose(s) | outcome |
|---|---|---|
| AAV | AAV, same serotype | Blocked |
| AAV | AAV, other serotype | Potentially useful |
| AAV | Non-AAV vector | Likely effective |
| Non-AAV vector | Non-AAV vector | Likely effective |
| AAV with immunosuppression | AAV with immunosuppression | Potentially useful |
| AAV delivered to privileged anatomical site | AAV delivered to privileged anatomical site | Likely effective |
As shown in Table 1, after a person has received systemic treatment with a specific AAV vector, then retreatment with the same vector, or a vector of the same serotype, is expected to be ineffective, because neutralizing antibodies will block vector delivery.
However, in theory that person could be treated with a different AAV vector, using a different serotype, or with a vector based on some other virus, or delivered via synthetic nanoparticle. There are several reasons why this approach is not widely used. A big reason is that the significant time and resources required to develop a single viral vector make it impractical to develop an entire separate product for the purpose of redosing. Another reason relates to the significant regulatory burden of bringing such a product to the clinic. Not all AAV serotypes are appropriate for delivery to specific target tissues, which means that the potential variety of AAVs available is limited.
Emerging Strategies to Overcome Immune Barriers
To circumvent these problems, many investigators are using immunosuppressive approaches to dampen preexisting immune responses or to forestall priming of new immune responses to AAV in gene therapy candidates. These approaches include small molecule drugs and/or monoclonal antibodies to suppress or eliminate antibody-producing B cells and/or plasma cells, as well as enzymatic treatment to degrade circulating antibodies. Several regimens have been tested in preclinical and clinical contexts, with some promising results indicating a potential to reduce or eliminate vector-specific neutralizing antibodies.
Finally, for some indications, AAVs are administered to immune-privileged sites, such as eye, lung, or brain. To protect against catastrophic autoimmunity, the human immune system has evolved brakes or barriers that limit and suppress immune responses in these tissues. This immune privilege has proven useful. For example, with retinal therapy, large numbers of people have been successfully treated first in one eye and then later treated with the same AAV product in the contralateral eye, without a significant loss of safety or efficacy.
Non-AAV Delivery Systems
Naturally occurring viruses are extremely diverse, with over 20 taxonomic phyla and over 300 taxonomic families. This natural diversity represents a breadth of opportunities for scientists looking to develop new gene therapy vectors, and in recent decades many such novel vectors have made it to the clinic. Many viruses have evolved to be relatively unaffected by neutralizing antibodies and novel gene therapy approaches may make re-dosing increasingly practical.
For this blog post, the FDA labels for all viral vector drug products with FDA marketing approval were analyzed (Table 2).
Table 2
| Product & Trade Name | Manufacturer | Vector / Modality | Pre-existing Immunity Contraindication* |
|---|---|---|---|
| IMLYGIC (talimogene laherparepvec) | Amgen | HSV | No |
| VYJUVEK (beremagene geperpavec) | Krystal Biotech | HSV | No |
| ADSTILADRIN (nadofaragene firadenovec-vcng) | Ferring | Adenovirus | No |
| PAPZIMEOS (zopapogene imadenovec) | Precigen | Adenovirus | No |
| ITVISMA / ZOLGENSMA (onasemnogene abeparvovec) | Novartis | AAV | No |
| LUXTURNA (voretigene neparvovec) | Spark | AAV | No |
| KEBILIDI (eladocagene exuparvovec) | PTC Therapeutics | AAV | No (not tested in subjects with antibodies)** |
| HEMGENIX (etranacogene dezaparvovec) | CSL Behring | AAV | No (further research needed)** |
| BEQVEZ (fidanacogene elaparvovec-dzkt) | Pfizer | AAV | yes |
| ELEVIDYS (delandistrogene moxeparvovec) | Sarepta | AAV | yes |
| ROCTAVIAN (valoctocogene roxaparvovec) | BioMarin | AAV | yes |
**FDA labels indicated that antibodies may be important but that more evidence is required to make a determination.
As of December 2025, the FDA has approved 11 in vivo viral vector gene therapies. Of the 11, four of them are not AAV-based; two are based on herpes simplex virus (HSV), and two are based on adenovirus. For these non-AAV therapies, FDA labels do not mention any exclusion or contraindication for treatment based on pre-existing antiviral antibodies. Of the seven AAV-based products, three of them do have specific exclusions or contraindications based on anti-AAV antibodies, and four do not. In some cases, the label notes that antibodies are not relevant due to administration in an immune-privileged location such as the eye or the intrathecal space.
Finally, recent developments in gene therapy have advanced the use of nanoparticles, in particular lipid-coated nanoparticles (LNPs), instead of viral vectors. Clinical and preclinical evidence so far suggests that most nanoparticle products do no induce antibodies that would interfere with subsequent redosing. Many developing genetic medicines involving gene editing and CRISPR-based technologies, for example, rely on LNPs for in vivo delivery.
Conclusion
While it is correct that many AAV therapies currently in the clinic do not allow for redosing or re-administration to the same person, many alternative approaches are being developed to allow redosing. These approaches have great potential to enhance efficacy and durability of gene therapy treatments for inherited and acquired diseases.
