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The FDA approval of for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy almost 4 years ago marked a turning point in gene therapy.

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

"Luxturna dramatically improves retinal sensitivity, resulting 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 at Oregon Health & Science University in Portland, in an interview.

"It is fascinating to hear about which real-life changes are most meaningful to patients," Christina Weng, MD, of Baylor College of Medicine in Houston, told 妖姬直播. Weng recalled how thrilled the family of a 5-year-old boy with Leber congenital amaurosis (LCA) type 2 was after treatment, "when he was able to go trick-or-treating on Halloween for the first time in his life."

With one dose per eye, voretigene neparvovec has the ability to "target the root source of the disease, and potentially permanently halt or dramatically reduce the progression of disease 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 Retina Society.

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 LCA, which has an estimated incidence of , and accounts for 5% of all inherited retinal diseases (IRDs) diagnosed.

Clinical signs of early IRD, such as nystagmus, decreased visual acuity, and poor night vision or dark adaptation, should prompt further testing, Pennesi told 妖姬直播. "Ultimately, genetic testing is absolutely critical for determining the etiology of the disease and whether there might be treatments (either approved or experimental)."

In addition, "ancillary testing -- especially optical coherence tomography (OCT), electroretinography, and fundus autofluorescence -- can be very helpful in providing additional insights, since there can be quite for the exact same mutation," noted Weng.

RPE65-associated IRD causes loss of visual function in two components: "a visual cycle blockade that is reversible with gene therapy and a cellular degenerative process which is unlikely to be reversible in its end stages," according to . The indication for voretigene neparvovec requires the presence of "viable retinal cells."

However, assessment of using OCT on human RPE65 gene mutants has not clearly linked the degree of visual function loss to age and OCT characteristics such as thickness. Thus, identifying patients likely to respond to gene therapy is left to the discretion of the treating provider, the review suggested.

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

"Second, refinements in surgical approach and instrumentation make subretinal delivery very safe and efficient to perform," Weng added. "As well, the Orbit Subretinal Delivery System, which allows the subretinal space to be accessed externally from the suprachoroidal space, rather than transvitreally, is being evaluated for some types of gene therapy. This approach would potentially avert some of the risks associated with a pars plana vitrectomy."

The most common potential adverse effects with voretigene neparvovec are associated with the surgery needed to inject the gene therapy: eye redness, transient blurriness, and acute inflammation, Weng said, which generally resolve within days to weeks.

"More rare adverse effects -- most related to surgery rather than to gene therapy itself -- include infection, macular hole, retinal detachment, elevated intraocular pressure, cataract formation, loss of vision, posterior inflammation, and retinal pigmentary changes," she continued.

Perifoveal atrophy is a known risk following subretinal injection of voretigene neparvovec, noted Qian. While longer-term studies are needed, "what we know for now is that it seems to occur within months of subretinal injection, and is intimately linked to the area of injection. Hence, care is needed in patient selection and in the planning of the injection site."

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

In addition to voretigene neparvovec, "University College London, University of Nantes, and University of Florida are among some of the institutions that are all independently working on enhancing and tweaking their developed gene product so as to improve the targeting of the AAV2 [adeno-associated virus 2] vector, maximize protein expression of the gene product, while keeping the risk of intraocular inflammation low," Qian told 妖姬直播. "Both AGTC and MeiraGTx/Janssen have completed phase I/II trials using their respective viral vectors with positive results. MeiraGTx/Janssen is also initiating phase III trials to study the use of an optimized version of their AAV to deliver the gene product."

"Previous have shown that supplementing orally with a 9-cis-retinyl acetate in lieu of the missing 11-cis-retinal resulted in improved visual acuity, visual field, and MRI functions in enrolled patients," Qian added. "This suggests that oral supplementation of synthetics may bypass the retinoid cycle blockade and promote continuation of the phototransduction cascade, and may also be a promising avenue of exploration in the future. Beyond LCA 2 and RPE65 gene mutations, in response to the challenge of treating autosomal dominant diseases with excess of gene product, exciting new discoveries, such as gene editing, CRISPR/Cas9, RNA therapy, and neuromodulation through optogenetics are also quickly evolving and adding new tools to the arsenal of therapies to treat IRDs."

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