Retinitis Pigmentosa

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies.

Retinitis pigmentosa is an inherited disease, in which mutations in different types of genes lead to the death of photoreceptors and the loss of visual function. Although retinitis pigmentosa is the most common type of inherited retinal dystrophy, a clear line of therapy has not yet been defined. In this review, we will focus on the therapeutic aspect and attempt to define the advantages and disadvantages of the protocols of different therapies. The role of some therapies, such as antioxidant agents or gene therapy, has been established for years now. Many clinical trials on different genes and mutations causing RP have been conducted, and the approval of voretigene nepavorec by the FDA has been an important step forward. Nonetheless, even if gene therapy is the most promising type of treatment for these patients, other innovative strategies, such as stem cell transplantation or hyperbaric oxygen therapy, have been shown to be safe and improve visual quality during clinical trials. The treatment of this disease remains a challenge, to which we hope to find a solution as soon as possible.

Retinitis pigmentosa (RP) poses a significant threat to eye health worldwide, with prevalence rates of 1 in 5000 worldwide. This genetically diverse retinopathy is characterized by the loss of photoreceptor cells and atrophy of the retinal pigment epithelium. Despite the involvement of more than 3000 mutations across approximately 90 genes in its onset, finding an effective treatment has been challenging for a considerable time. However, advancements in scientific research, especially in gene therapy, are significantly expanding treatment options for this most prevalent inherited eye disease, with the discovery of new compounds, gene-editing techniques, and gene loci offering hope for more effective treatments. Gene therapy, a promising technology, utilizes viral or non-viral vectors to correct genetic defects by either replacing or silencing disease-causing genes, potentially leading to complete recovery. In this review, we primarily focus on the latest applications of gene editing research in RP. We delve into the most prevalent genes associated with RP and discuss advancements in genome-editing strategies currently employed to correct various disease-causing mutations.

A small azobenzene photoswitch molecule (KIO-301), designed to confer light responsiveness to retinal ganglion cells, was evaluated for safety and feasibility in a first-in-human, phase 1, gene-agnostic, open-label, dose-escalation clinical trial in individuals with advanced retinitis pigmentosa (RP). KIO-301 was administered by intravitreal injection to 12 eyes of 6 participants. The primary outcome was ocular and systemic safety over 30 days. Secondary and exploratory assessments included functional vision testing, visual acuity, kinetic visual field, functional magnetic resonance imaging and participant-reported outcomes. The primary safety outcome was met, with no serious adverse events or dose-limiting toxicities observed at any point. No drug-related intraocular inflammation occurred, and all ocular adverse events were mild and procedure-related. Exploratory assessments identified variation in light perception and functional vision measures in some participants. Light-evoked blood-oxygen-level-dependent signal changes in visual cortical regions were observed following dosing and showed a temporal pattern compatible with pharmacodynamic activity. Participant-reported quality-of-life scores varied over time. In this small, nonrandomized phase 1 study in individuals with late-stage RP, intravitreal KIO-301 demonstrated an acceptable safety and tolerability profile, supporting the feasibility of photoswitch therapy in advanced RP, and motivating further evaluation in larger trials. ClinicalTrials.gov identifier: NCT05282953.