From Lab to Clinic: Cyclodextrins and Stargardt Disease Research

Stargardt macular dystrophy, also known as Stargardt disease (STGD1), is an inherited macular dystrophy characterized by progressive vision loss. It results from pathogenic sequence variants in the ABCA4 gene1. Here are some therapeutic approaches being explored for Stargardt disease:

1. Pharmacological Therapies: Cyclodextrins: These cyclic sugar molecules have been investigated for their potential to reduce lipofuscin accumulation in the retinal pigment epithelium (RPE). Lipofuscin buildup contributes to disease progression. Cyclodextrins may help remove toxic compounds associated with Stargardt disease.
2. Gene Therapies: Antisense Oligonucleotides (ASOs): Researchers at Radboud University Medical Centre in the Netherlands have developed an RNA therapy using ASOs to rescue splice defects within the ABCA4 gene. This strategy aims to correct aberrant transcripts and improve gene function.
3. Cellular Therapies: Stem Cell-Based Approaches: While still in the early stages, stem cell-based therapies hold promise for replacing damaged retinal cells in Stargardt disease.
4. Genetic Therapies: Whole Gene Replacement: Excitingly, novel approaches aim to replace the entire 6.8 kb ABCA4 open reading frame, potentially restoring normal gene function.

REV-0100 (sulfobutyl-ether-beta-cyclodextrin), developed by Revision Therapeutics was awarded both Orphan Drug Designation (ODD) and Rare Pediatric Disease (RPD) designation by the US Food and Drug Administration. REV-0100 works by reducing levels of a toxic lipid called lipid bisretinoid, which accumulates within the retina in material called lipofuscin. This accumulation happens much more quickly in people with Stargardt disease, leading to retinal cell death and retinal degeneration, which eventually results in permanent central blindness. By reducing levels of the abnormal accumulation of toxic lipid bisretinoid, REV-0100 is being developed as a treatment to stave off or prevent central blindness in people diagnosed with the ABCA4 gene mutation that leads to Stargardt disease.

Aequus Pharmaceuticals Inc. and reVision Therapeutics, Inc. (“reVision”) announced a collaboration on the development of a therapy for Stargardt disease. Aequus is a specialty pharmaceutical company with multiple commercial eye care products and reVision is a privately-held, biopharmaceutical company focused on the development and commercialization of innovative therapies for rare ocular diseases. The agreement allows Aequus the option to acquire North American commercial rights to REV-0100, reVision’s proprietary Stargardt disease program.

Stargardt disease is a devastating genetic disorder that affects central vision in children and adults, often leading to blindness. There are currently no approved treatment options.?REV-0100 is based on important discovery research from?Weill?Cornell Medicine?in?New York City?that shows REV-0100 can reduce elevated levels of toxic lipid material called lipofuscin in pre-clinical studies. reVision is thus poised to demonstrate the benefit of reducing levels of lipofuscin to alter the course of Stargardt disease progression.

The US Food and Drug Administration has already designated REV-0100 as an Orphan Drug and a Rare Pediatric Disease Drug for?the treatment of Stargardt disease. These designations support accelerated development of REV-0100, expediting review and evaluation amongst other benefits, including Orphan Drug market exclusivity upon successful program completion. In addition, the drug substance has an established safety profile and is manufactured to GMP standards, potentially reducing safety risk and shortening the development timeline.

As part of the option terms, Aequus will make an equity investment in reVision with the option to fully fund the development program in return for the North American commercial rights. Funds from the initial investment are earmarked to cover the costs of a pre-clinical toxicology study for REV-0100, which we begin in the near term.

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In the coming weeks, we will continue focusing on using cyclodextrins as active ingredients, disease by disease. Stay tuned!

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