Carel B. Hoyng, MD, noted that investigators have developed an RNA therapy to stop the progression of the disease, which ultimately leads to legal blindness.
Reviewed by Carel B. Hoyng, MD
Investigators in the Netherlands are focused on finding a treatment for Stargardt disease, an inherited progressive retinal disorder that affects about 1 in 10,000 individuals worldwide.
They have developed a unique therapeutic approach, an RNA therapy, to stop the progression of the disease, which ultimately leads to legal blindness, according to Carel B. Hoyng, MD, professor of Ophthalmology and shareholder and cofounder of Astherna with Rob Collin, PhD, professor of Molecular Therapy for Inherited Retinal Diseases, both from Radboud University Center, Nijmegen, Netherlands.
Hoyng explained at the Bascom Palmer Eye Institute’s 19th annual Angiogenesis, Exudation, and Degeneration 2022 Virtual Edition that mutations in the ABCA4 gene interrupt the visual cycle in Stargardt disease, which usually affects people in the first or second decade of life. That disruption in the visual cycle affects production of proteins and ultimately leads to lipofuscin accumulation in the retinal pigment epithelium (RPE). The goal is to restore the appropriate protein production in the visual cycle of these patients.
Stem cell, gene, and pharmacologic therapies have been considered for Stargardt disease. Among these, hESC-RPE cells are in trials as is the gene therapy SAR422459 in the StarGen trial. Numerous pharmacologic therapies are also being evaluated.
Antisense oligonucleotides (AONs)
AONs, a new area of drug development, can prevent the gradual decline in vision that characterizes Stargardt disease by binding to the targeted RNA. These synthetic RNA molecules work to restore the proteins that are affected by the disease. This approach has already been shown to be promising in Leber congenital amaurosis, another inherited retinal disease. In these patients, 8 intravitreally AON-treated eyes had a clinically meaningful (p = 0.001) improvement in vision compared with the untreated contralateral eye 3 months after treatment,1 Hoyng said.
This therapy is advantageous in that it gets to the inherited root of the disease, ie, the flaws in the RNA, and the small size of the molecules allows them to access the targeted retinal cells.
In a study of AONs in Stargardt disease,2 in which Hoyng participated, the investigators sought to identify missing heritability in these patients. They sequenced ABCA4 in 8 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. In two-thirds of cases, they identified 1 known and 5 novel deep-intronic variants. AONs introduced to correct splice defects resulted in partial correction of the defects in the ABCA4 gene, thus demonstrating the potential of this therapy.
“The importance of this research is that it tackles the root cause of Stargardt disease,” Hoyng concluded.
1. Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med published online Dec 17, 2018; doi: 10.1038/s41591-018-0295-0
2. Sangermano R, Garanto A, Khan M, et al. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. Gen Med 2018; DOI: 10.1038/s41436-018-0414-9