Retinagenix Therapeutics is a clinical stage biopharmaceutical company devoted to addressing the large and expanding unmet medical needs in genetically determined orphan diseases of the eye. We are part of the BridgeBio family and are committed to developing transformative therapies to change lives.
We are developing our lead product candidate, RGX-001 (Zuretinol Acetate), for the treatment of vision threatening diseases including Retinitis Pigmentosa, Leber Congenital Amaurosis and age-related defects in dark adaptation (including Early Age-Related Macular Degeneration (AMD).
Our rare inherited retinal disease programs focuses on disease specifically caused by mutations of Retinal Pigment Epithelium Protein 65 (RPE65) or Lecithin: Retinol Acyltransferase (LRAT). These mutations cause retinal degeneration and progressive visual loss that lead to eventual blindness.
Our therapeutic strategy is to use a small molecule approach to replace the key biochemical component of the visual cycle that is deficient in these patients (either due to inherited genetic mutations or age-related retinal changes). Our pro-drug is designed to bypass the site of enzyme disfunction
Science
INHERITED RETINAL DISEASES
Inherited retinal diseases (IRDs) include a collection of heterogeneous processes characterized by variable dysfunction of rods and cones, the photoreceptors of vision. Genes that are mutated in IRDs encode proteins that lead to dysfunction through multiple mechanisms, often interfering with normal function of the visual cycle. The visual cycle is a biochemical loop which regenerates necessary visual pigments – chromophores – that are required for the transduction of light stimulation into an electrical signal. It is the action potential so generated by retinal ganglion cells that initiates the process of central neural processing which unfolds into vision. Key enzymes in this cycle are retinal pigment epithelium (RPE)-specific protein 65 kDa (RPE65) and lecithin:retinol acetyltransferase (LRAT), which are encoded by the RPE65 and LRAT genes, respectively.
In the normal functioning visual cycle, vitamin A from serum is taken up by retinal pigment epithelium (RPE) cells to generate a crucial metabolite, 11-cis-retinal. Photoreceptors use 11–retinal to generate the photopigment rhodopsin by complexing with the protein opsin. Rhodopsin absorbs light striking photoreceptors, and initiates processing essential for vision.In a normal eye, following signal transduction, the cis-retinal is converted to all trans-retinal, which requires a series of conversions including reduction to all trans-retinol, esterification, isomerization from trans back to cis along with hydrolysis back to the alcohol. The alcohol then undergoes oxidation to an aldehyde, 11-cis-retinal, again forming a complex with opsin. Mutations in either the RPE65 or LRAT genes disrupt key steps in regenerating 11-cis-retinal, leading to a deficiency in this molecule declared as inadequacy of signal transduction. This dysfunction is followed by progressive deterioration of photoreceptors expressed as loss of both functional vision and visual function, leading eventually to blindness.
AGE-RELATED DARK ADATPATION DEFECTS INCLUDING AMD
There are currently no approved therapies to treat Early Age-Related Macular Degeneration (AMD). AMD is heralded by defects in dark adaptation. Basic and clinical science studies have demonstrated this defect is due to slowing of the visual cycle, namely attenuated regeneration of 11-cis-retinal. With less chromophore available this leads to increased free opsin in the photoreceptor outer segments. Free is not as stable as rhodopsin allowing it to stimulate the visual transduction cascade without being activated by light. This increases the metabolic activity within these cells, and this can lead to both increased noise in the visual transduction system and increased metabolic products requiring increased activity within the retinal pigment epithelial cells (RPE) and thus increasing the RPE’s need to discharge these waste products, leading to increased drusen, a major risk factor for vision loss due to AMD.
THERAPEUTIC STRATEGY
We are evaluating 9-cis-retinyl acetate (Zuretinol Acetate, RGX-001)) as a way to provide 9-cis-retinol to replace deficient 11-cis-retinol in the visual cycle. The 9-cis-retinol is oxidized to 9-cis-retinal that acts as the replacement for 11-cis-retinal, to complex with opsin for photo signal transduction. We are working to develop our drug as an oral therapy, rather than a locally applied or injected product, to potentially treat the entirety of retina in each eye concurrently. RGX-001 has demonstrated a favorable tolerability profile in clinical studies to date. It has been administered to 144 subjects in 8 clinical trials with doses ranging from 1.25 mg/m2 to 60 mg/m2. In the trials treating IRD patients, we have observed clinical activity in the majority of RPE65 or LRAT mutation patients who have received RGX-001. Subjects showed improvements characterized by either expansion of visual field or improved visual acuity, and in most patients, both. RGX-001 has orphan designations from the U.S. and European regulatory authorities, as well as Fast Track status in the United States. In one small randomized, placebo-controlled, proof of concept trial in 45 early AMD patients, Subjects treated with RGX-001 showed measurable improvement in dark adaptation vs placebo.
(Modified from von Lintig et al. 2010; IRBP: interphotoreceptor retinoid binding protein; IPM: interphotoreceptor matrix; ROS: rod outer segment)
About Us
Zuretinol acetate was conceptualized and initially developed at the University of Washington by Drs. Kris Palczewski and David Saperstein. The program was acquired in 2020 by Retinagenix Holdings, LLC, formed to bring this potentially vision-saving investigational therapy to patients.
Leadership
LEADERSHIP
Marco Antonio Northland, MBA
DAVID A SAPERSTEIN, MD BD
Parent Company
Retinagenix Therapeutics IS A MEMBER OF THE BRIDGEBIO FAMILY
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development.
Publications
Contact
75 Federal Street
San Francisco, CA 94107
421 Kipling Street
Palo Alto, CA 94301
55 Fifth Avenue, Suite 1805
New York, NY 10003
