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Eyes On Pharma Blog 

Eyes on Gene Therapy - The Background

Gene therapy as a whole is a relatively new approach to disease treatment and is effectively irreversible after administration. Some theorize that unexpected or delayed side effects could emerge years after initial exposure to the genetic material or its delivery vector. While that is possible, Regenxbio has generated multiple years’ worth of clinical follow-up data across its various programs with no evidence of such adverse events thus far. Technology licensee Novartis has also achieved FDA approval with Zolgensma as proof-of-concept. Our next post will have some additional information on the FDA look into potential side effects of genetic medicines.

Quick Refresher

Genetic diseases are the result of mutated DNA, which is translated into irregular and dysfunctional protein products. DNA, our genetic code, serves as ‘instruction’ for producing functional units required for life. It can self-replicate by the actions of the enzyme DNA polymerase, which enables parent cells to pass on identical DNA copies to progeny cells.

DNA cannot be read directly through the source of genetic information, but rather, it is transcribed by the enzyme RNA polymerase into a more functional form, a temporary but more ‘workable’ complimentary copy of DNA. This template is translated by molecular machines called ribosomes that chain amino acids together in order based on the nucleotide sequence of mRNA. Proteins are the result of this translation and serve a vast array of functional purposes in the body.

If an individual is born with a genetic mutation, the DNA sequence shared between all cells is altered. Some mutations are harmless, while others can be deadly if they interrupt the normal protein transcription and function.

Source: Stifel 31 Oct 23


Gene Therapy

A single gene mutation is ascribed to 80% of known rare diseases. Many current therapeutic approaches are focused on the downstream outcome of the mutation, aiming to replace or supplement the missing protein by using a different agent to mimic its biological function. They are less efficient than therapies that pursue an upstream target with often a clear root cause of the disease, such as Gene Therapy.

Gene Therapy produces a therapeutic effect by transferring genetic material into living cells, altering gene expression, or restoring missing biological functions at their source. The dysfunctional cells are ‘rewired’ and a long-term duration of response with potential cure induced.

There are two primary methods of administration: ‘in vivo’ and ‘ex vivo’. The former uses modified viruses or other vectors, injecting them into the body to deliver genes directly to cells. The latter removes the patient’s own cells, manually modifying specific genes in a lab, and then returning them to the body.

Source: Stifel 31 Oct 23


In Vivo Gene Therapy and AAV vectors 

Adeno-associated viruses, AAV vectors, are among the most well-developed and validated gene therapy approaches.

AAVs are tiny icosahedral-shaped viral particles. They possess genetic material, single-stranded DNA and are unable to reproduce or replicate on their own. They infect other cells by ‘hijacking’ the host’s existing cellular machinery in order to copy themselves. Unable to infect the host fully on their own, AAVs rely on co-infection with a different family of viruses called adenoviruses (e.g., common cold). AVVs also require specific adenoviral genes to be present (e.g., E1, E4) to replicate. Because AAVs prove to be ‘replication incompetent’, they have become almost undetectable by human hosts. The immune response against them remains relatively mild despite the presence of the adenoviral genes needed for replication. Due to their inherent biological ability to transport genetic material and their low immunogenicity, AAVs are ideally suited to serve as vectors (transfer vehicles) for the delivery of novel genes in the treatment of genetic disorders. The modification of the ‘normal’ (wild-type) genetic code of existing AAVs enables scientists to create new AAVs to carry beneficial human genes. These are referred to as AAV or rAAV.

AAV Gene Therapy has inherently little immunogenicity and has a very low risk of spontaneous pathological reversion. With other therapies that use live viruses but in a ‘weakened’ state (e.g., attenuated vaccines), there lies the small risk that these viruses can spontaneously revert to their WT (wild-type) virulent forms and cause disease symptoms. With rAAVs, however, so much of their WT genome has been removed that reversion risk is mostly negligible.

AAVs come in a wide variety of natural serotypes, each of which has a particular tropism (preferential targeting of certain cell/tissue types). By modifying the AAV capsid in the lab (e.g., causing it to display a specific ligand, altering binding sites), these natural tropisms can be made even more selective to hone in on a very particular cell/tissue type so the functional copy of the gene can be more easily delivered to the relevant targets.

There are 13 ‘natural’ serotypes, labeled AAV1-13. Novel AAV vectors can be synthetically created either through hybridizing different serotypes or editing the Cap gene of a particular serotype. The engineered AAV vector may have enhanced tropism for a particular tissue, be resistant to degradation, or possess other beneficial qualities.

They can naturally infect both dividing and quiescent (non-dividing) cells, enabling gene delivery to a more diverse range of cell types. Certain alternative viral vectors (e.g., retroviruses) can only infect dividing cells, limiting effectiveness in longer-lived cell types.

The AAV genome is only -4.7 kb long, notably small for relevant genetic sequences. WT AAV genes themselves contain large amounts of overlapping sequences in order to fit, but this biological workaround is often not possible with longer human genes. Thus, rAAVs can only deliver short human transgenes.

The WT AAV genome can integrate with the human host’s genome at chromosome 19 when not being actively transcribed – this means that when a cell divides and replicates its DNA to pass to its progeny, the AAV genome is also replicated and persists. However, rAAV lacks the AAV Rep gene, which is required for host genome integration. Thus, when cells divide, the episomal rAAV genome is not copied into progeny cells and can be diluted in concentration over time – this drawback is more prevalent in cell types that divide rapidly but becomes less of a concern in long-lived cell types.

Source: Stifel 31 Oct 23


AAVs have low immunogenicity and typically only produce a mild immune response, a net positive overall, as they are less likely to be detected by the body; however, infection with WT AAV is very common. As a result, a sizable number of individuals may naturally develop neutralizing antibodies (Nabs) to specific AAV stereotypes as they age and are exposed.

These Nabs will naturally target rAAVs of the corresponding serotype as well, diminishing their therapeutic potential. Therefore, some degree of immune suppression may be required to deplete these Nabs. AAV gene therapy may be better suited for younger patients who have yet to develop AAV Nabs.

 Eyes on Regenxbio

Because of their rich pipeline and years of experience, we thought it would be interesting to take a closer look at their technology and competitive edge. Regenxbio’s recombinant AVV vectors use a 3-plasmid co-infection system, which allows for the transcription of longer genes and safer replication. Their proprietary NAV technology platform underpins their broad therapeutic pipeline and is among the most well-developed clinical research processes with scalability to commercial readiness. The diagram below provides an overview of the Regenxbio platform for AAV creation.


The NAV technology platform has been widely adopted and validated by several major players in gene therapy space including Novartis, Astellas, Lilly, Ultragenyx, uniQure and Rocket Pharma. Indications cover multiple diseases in Ophthalmology, CNS, Muscle and other therapeutic areas.

Regenxbio also has numerous patents to protect its technology and products as outlined in the graphics below.

Source: Stifel 31 Oct 23

Source: Stifel 31 Oct 23



Regenxbio Commercial Risks & Advantages

As approved gene therapies are still rare, the commercial landscape is highly uncertain. Payers may be unwilling to cover a more expensive, ‘one-time’ treatment when other less expensive options are available, particularly in wAMD and DR. The few currently marketed gene therapies can serve as initial examples of where commercial hurdles lie. Therapies that directly address rare single-gene mutations are logical approaches and will be more difficult for payers to argue against.

Regenxbio has no wholly-owned FDA-approved products to date for revenue generation to offset extensive clinical trial costs. Even if approved, expenses could increase beyond expectations if the FDA requires post-marketing trials or REMS programs. Despite having no revenues from direct sales of products, Regenxbio has generated significant revenues to fund operations from licensing its NAV Technology Platform. The company has an operational cash runway into 2025.

Gene therapy products are more complex to manufacture than most other chemical pharmaceuticals, and their physical and chemical properties cannot be fully characterized. Minor deviations from the procedure could result in product defects. Regenxbio relatively recently completed the implementation of a bioreactor suspension process (NAVXpress) in place of its initial Hyperstack adherent process, which has increased yield and is highly automated to reduce batch variation.

Though there are a number of other companies also focused on developing gene therapies for the same indications Regenxbio has prioritized, their methods differ somewhat. There are rival AAV vectors along with techniques for directly modifying genes. However, even if multiple competitors use AAVs, the specific vectors used can vary in tropism and delivery success. The transgene packages can also differ within the same indication, and genetic material optimization could result in efficacy differences key to successful commercialization.

Next up – we’ll take a look at what’s approved and what’s coming through the pipeline.

If you are interested in following all the happenings in the Genetic Medicines area - check out our Syndicated Alert which provides current research and insights on the are in a bi-weekly email alert. Check it out here.

Please refer to the following articles for more details on the information shared in this article, plus more on Cell and RNA Therapies, and select companies covered by our network.


ASGCT - Citeline Report: Gene, Cell, + RNA Therapy Landscape Report, Q3 2023 Quarterly Data Report

Not included in post but a great Deep Dive Report in PharmaTell Studio :Genomic Medicine Deep Dive - Redrawing Frontiers

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