Retinal Gene Therapy Advancing, Emphasis Now On Immune Response

Adeno-associated viruses, computer illustration. Adeno-associated viruses (AAVs) are the smallest known viruses to infect humans. They do not cause diseases, and only provoke a mild immune response. Because they incorporate their genetic material into a specific location within the hosts genome, they have potential as a vector for gene therapy. The spiky protein coat (capsid) protects the genetic material.
Researchers evaluate adeno-associated virus-related immune responses, toxicity and inflammation across various studies on retinal gene therapy.

Genetic therapies for degenerative retinal diseases are now being more widely explored, as clinicians and researchers seek to address underlying genetic defects, and this focus is supported by advances with gene transfer using viral vectors, according to a recent comprehensive review and analysis of gene therapy by investigators in Germany and the United Kingdom.1

The review explains that adeno-associated virus (AAV) vectors have been demonstrated to be optimal in gene therapy for degenerative disorders such as retinitis pigmentosa — AAV is non-pathogenic, replication-deficient, and favors retinal pigment epithelium, the investigators wrote.1 One such gene therapy, voretigene neparvovec-rzyl, was approved by the US Food and Drug Administration on Dec.18, 2017.2

However, this set of viruses does not completely avoid the immune system, and it can be challenging to manage ocular inflammation while safeguarding the effectiveness of gene transfer, according to the review authors.1

Although the eye is uniquely immune-privileged and can moderate pro-inflammatory responses, local or systemic immune responses can be caused by several factors: the eye’s physical blood-tissue barriers can be damaged by the underlying degeneration being treated, barriers are broken by the gene therapy injection itself, and vector particles injected into the subretinal space may reflux into the vitreous and anterior chamber, escaping the ocular micro-environment through the Schlemm’s canal.1

“Analyses of sequential AAV administrations show that the route of vector administration and the vector dose are critical determinants of the humoral immune response and the transduction efficiency of bilateral gene therapy,” according to the review.1

Previous studies demonstrated that ocular immune responses were more likely when the dosage of injection was greater than 1 x 1011 vector genomes (vg) per eye. Vector-derived antigen may reach a critical threshold to activate immune responses leading to gene therapy associated uveitis (GTAU). With regard to vector delivery, subretinal injection produces fewer vectors than intravitreal injection in the aqueous humor. Systemically, subretinal injection causes almost no AAV vector load in the blood, or vector distribution into the spleen and certain lymph nodes.1

Strategies to lessen AAV-induced immune response include modifying the vector, and administering immune-modulating medicines along with AAV. Examples of vector modification include altering the capsid protein’s coding sequence, with pools checked for variants that can escape neutralizing antibodies, or using multiple AAV serotypes in random order. A potential immunosuppressive strategy is to use imlifidase (IdeS) to decrease anti-AAV antibodies, and thus reduce pre-existing immunity to AAV. Another approach may be to co-administer the immune suppressant compound rapamycin, “encapsulated in synthetic vaccine particles” along with AAV to reduce a capsid-specific immune response.1

The review authors explain that the next steps in genetic therapy include identifying which ocular cells are primary sensors for AAV — cells that begin the immune response in the retina and other eye compartments. “The identification of these cells would allow a detailed investigation of the cellular receptors and signaling pathways expressed by them that mediate AAV uptake and/or trigger innate immune responses to the vector,” the researchers added.1

In addition, they advise a look into whether naïve B and T cells are primed in the eye locally, or in secondary lymph nodes after draining from the canal of Schlemm. Overall, a deeper knowledge of the eye’s immunological processes prompted by gene therapy is necessary to further reduce risks, and expand improving results of treatment with AAV vectors.1

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


1. Bucher K, Rodriguez-Bocanegra E, Dauletbekov D, Fischer MD. Immune responses to retinal gene therapy using adeno-associated viral vectors — Implications for treatment success and safety. Prog Ret Eye Res. Available online October 15, 2020. doi:

2. Fischer A. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. US Food and Drug Administration. December 17, 2017. Accessed November 5, 2020.