SpliceBio Initiates First-in-Human Trial of Dual AAV Gene Therapy for Stargardt Disease
Key Insights
SpliceBio (search) has dosed the first patient in its Phase 1/2 ASTRA study evaluating SB-007, a novel dual AAV vector gene therapy for Stargardt disease (search), which has no approved treatments.
The therapy uses innovative protein splicing technology to overcome size limitations of traditional gene therapy, potentially restoring full-length ABCA4 (search) protein expression in all Stargardt patients regardless of their specific mutations.
Alongside the ASTRA clinical trial, SpliceBio (search) is conducting the POLARIS natural history study to better understand disease progression and optimize patient selection for accelerated enrollment into therapeutic trials.
Barcelona-based SpliceBio (search) has announced the dosing of the first patient in its Phase 1/2 ASTRA clinical trial evaluating SB-007, a pioneering dual adeno-associated viral (AAV) vector gene therapy for Stargardt disease (search). This milestone marks a significant advancement in addressing an inherited retinal disorder that currently has no approved treatments.
Stargardt disease (search), the most common form of inherited juvenile macular degeneration, affects approximately 1 in 8,000 to 10,000 individuals. The progressive retinal dystrophy is caused by mutations in the ABCA4 (search) gene, which has previously been challenging to target with conventional gene therapy approaches due to its large size.
Innovative Protein Splicing Technology
SB-007 employs a novel protein splicing approach to overcome the size limitations of traditional gene therapy vectors. The technology utilizes split inteins – auto-processing protein domains – that enable the delivery of large genes through a dual AAV vector system.
"Stargardt disease (search) has remained elusive to gene therapies due to the large size of the ABCA4 (search) gene. SB-007 is the first gene therapy in clinical development designed to restore expression of the full-length ABCA4 protein across all Stargardt disease patients, regardless of their mutations," explained Miquel Vila-Perelló, PhD, Chief Executive Officer and co-founder of SpliceBio (search).
The company's technology is based on research from Tom Muir and colleagues, who developed mutated split inteins for DNA-Polymerase III (DnaE) that eliminate sequence preferences at extein residues adjacent to the splice site. This innovation allows for the repair of very large genes through protein splicing.
The ASTRA Clinical Trial
The Phase 1/2 ASTRA study will evaluate both the safety and efficacy of a single subretinal dose of SB-007 in patients with Stargardt disease (search). The U.S. Food and Drug Administration (FDA) cleared the investigational new drug (IND) application for SB-007 in December 2023, and the therapy has received orphan drug designation in both the United States and Europe.
"Stargardt disease (search) is a devastating inherited retinal disorder with no approved treatments available," said Paul Yang, MD, PhD, chief of the Paul H. Casey Ophthalmic Genetics Division at Oregon Health & Science University Casey Eye Institute (search) and principal investigator of the ASTRA study. "The initiation of this study with the dual AAV vector gene therapy, SB-007, represents a critical advancement in finding a potential treatment option for patients with this disease."
Complementary Natural History Study
In parallel with the ASTRA trial, SpliceBio (search) launched the POLARIS study in March 2024 – a company-sponsored natural history study designed to evaluate disease progression in Stargardt patients. This complementary research aims to refine endpoints and streamline eligibility criteria for accelerated enrollment into the Phase 1/2 ASTRA study.
The POLARIS study will enable more precise diagnoses and rigorous disease monitoring, potentially offering Stargardt disease (search) patients faster access to innovative therapies. SpliceBio (search) continues to enroll patients in this natural history study while advancing the ASTRA clinical trial.
Potential Impact for Patients
If successful, SB-007 could represent a breakthrough for Stargardt disease (search) patients who currently have no treatment options. The therapy's ability to potentially restore expression of the native full-length ABCA4 (search) protein in the retina addresses the fundamental genetic cause of the disease.
SpliceBio (search) leadership has indicated that the company will share data from both the ASTRA and POLARIS studies at scientific conferences as the research progresses. The development of SB-007 highlights the potential of protein splicing technology to address rare genetic disorders caused by mutations in large genes that have previously been beyond the reach of conventional gene therapy approaches.