Clinical challenges: gene therapy for inherited retinal diseases


FDA approval of voretigene neparvovec (Luxturna) for the treatment of patients with confirmed biallelism RPE65 Almost 4 years ago, mutation-associated retinal dystrophy marked a turning point in gene therapy.

Since then, clinicians have witnessed the positive impact gene therapy has had on the lives of patients and their families.

“Luxturna dramatically improves retinal sensitivity, which results in improved night vision in most patients and even visual acuity in some patients,” said Mark Pennesi, MD, PhD, of the Casey Eye Institute Ophthalmic Genetic Clinic of Oregon Health & Science University in Portland, in an interview.

“It is fascinating to hear which changes in real life are the most significant for patients,” said Christina Weng, MD, of Baylor College of Medicine in Houston. MedPage today. Weng recalled how thrilled the family of a 5-year-old boy with Leber’s congenital amaurosis (ACL) type 2 was after the treatment, “when he was able to participate in Halloween for the first time in his life.” .

With one dose per eye, voretigene neparvovec has the ability to “target the source of the disease, and potentially permanently stop or dramatically reduce disease progression from an early age in eligible patients,” noted Cynthia X. Qian, MDCM, of the University of Montreal, who is a member of the Canadian Ophthalmological Society and the Canadian Retinal Society.

The subretinal gene therapy trials began with the discovery of RPE65 variants and the role of biallelic RPE65 gene mutations in rare types of retinitis pigmentosa and in ACL, the incidence of which is estimated to be two to three per 100,000 people, and accounts for 5% of all hereditary retinal diseases (RDI) diagnosed.

Clinical signs of early DRI, such as nystagmus, decreased visual acuity, and poor night vision or dark adaptation, should prompt further testing, Pennesi said. MedPage today. “Ultimately, genetic testing is absolutely essential in determining the etiology of the disease and whether there might be any treatments (approved or experimental).”

In addition, “ancillary tests – particularly optical coherence tomography (OCT), electroretinography, and fundus autofluorescence – can be very useful in providing additional information, as there may be heterogeneous phenotypes for the exact same mutation, ”Weng noted.

RPE65-the associated IRD causes a loss of visual function in two components: “a blockage of the visual cycle which is reversible with gene therapy and a cellular degenerative process which is unlikely to be reversible in its terminal stages”, according to an opinion. The indication of voretigene neparvovec requires the presence of “viable retinal cells”.

However, the evaluation of photoreceptor health using OCT on human RPE65 genetic mutants did not clearly relate the degree of loss of visual function to age and characteristics of OCT such as outer nuclear layer thickness. Thus, the identification of patients likely to respond to gene therapy is left to the discretion of the treatment provider, the review suggested.

Advances in subretinal delivery of gene therapy include the use of more sophisticated vectors to deliver the transgene into the host cell and nucleus, Weng said. MedPage today. “Today, we have the ability to modify viral vectors via rational design or directed evolution to confer an enhanced transduction, tropism and / or immunogenicity profile. There are also non-vector options today. viral, such as nanoparticles or iontophoresis. “

“Second, improvements in the surgical approach and instrumentation make subretinal childbirth very safe and efficient,” Weng added. “Likewise, the Orbit subretinal delivery system, which provides access to the subretinal space externally from the suprachoroidal space, rather than transvitreally, is being evaluated. for certain types of gene therapy. This approach would potentially avoid some of the risks associated with pars plana vitrectomy. “

The most common potential side effects with voretigene neparvovec are associated with the surgery needed to inject the gene therapy: redness of the eyes, transient blurring, and acute inflammation, Weng said, which usually go away within days to weeks.

“The rarer side effects – most related to surgery rather than the gene therapy itself – include infection, macular hole, retinal detachment, high intraocular pressure, cataract formation, vision loss, posterior inflammation and retinal pigment changes, “she continued. .

Perifoveal atrophy is a known risk after subretinal injection of voretigene neparvovec, Qian noted. While longer term studies are needed, “what we know so far is that it appears to occur in the months following subretinal injection and is intimately linked to the area. injection. injection site. “

“There are only preliminary reports in a small cohort of patients and even many of these patients still reported overall functional improvement,” Pennesi said. “A larger retrospective study of all patients is needed to determine the true prevalence.”

In addition to voretigene neparvovec, “University College London, the University of Nantes and the University of Florida are among some of the institutions which are all working independently on the improvement and adjustment of their developed gene product in order to improve AAV2 targeting [adeno-associated virus 2] vector, maximize protein expression of the gene product, while keeping the risk of intraocular inflammation low, ”said Qian MedPage today. “AGTC and MeiraGTx / Janssen have completed Phase I / II trials using their respective viral vectors with positive results. MeiraGTx / Janssen is also entering phase III trials to investigate the use of an optimized version of their AAV to deliver the gene product. “

“Previous phase I studies of QLT091001 showed that oral supplementation with 9-cis-retinyl acetate instead of the missing 11-cis-retinal resulted in improved visual acuity, visual field and MRI functions in enrolled patients, ”a added Qian. “This suggests that oral supplementation with synthetics may bypass the blockage of the retinoid cycle and promote the continuation of the phototransduction cascade, and may also be a promising avenue of exploration in the future. Beyond ACV 2 and RPE65 gene mutations, in response to the challenge of treating autosomal dominant diseases with excess gene product, exciting new findings, such as gene editing, CRISPR / Cas9, RNA therapy and optogenetic neuromodulation are also evolving rapidly and add new tools to the arsenal of therapies to treat RDI.

  • Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.


Pennesi said he worked as a consultant for Allergan Retina, Biogen / Nightstar and REGENXBIO, and Spark Therapeutics.

Weng revealed his relationships with Alcon, Alimera Sciences, Allergan / AbbVie, the Dutch Ophthalmic Research Center, Novartis, Regeneron and REGENXBIO.

Qian said he worked as a consultant for Allergan, Bayer, Novartis and Roche.


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