Recent advances in genetic sequencing have identified an increasing number of rare heterozygous toxic gain-of-function (TGOF) mutations. These mutations pose significant challenges in developing therapies due to the need for allele-selective approaches that target only the mutant allele.
Antisense oligonucleotide (ASO) technology offers a promising solution for allele-selective targeting. However, clinical trials for TGOF patients are often hindered by the difficulty in finding sufficient patients with the same gene variant.
In a commentary published in Nucleic Acid Therapeutics, Dr. Stanley T. Crooke proposes a cost-effective regulatory strategy to address this challenge. The approach involves conducting a single Phase 3 study in which patients are stratified by disease severity and variant. Each variant would receive a specific allele-selective ASO.
After the study, data from all variant-selective treatments would be aggregated and compared to placebo. This would allow for evaluating the safety and efficacy of multiple ASOs in a single trial.
Dr. Crooke emphasizes the potential for this strategy to make the development of allele-selective ASOs more feasible, enabling the treatment of a broader range of patients with TGOF mutations. As more patients undergo whole genome sequencing, the prevalence of TGOF heterozygous mutations is expected to rise, highlighting the need for innovative regulatory approaches to facilitate the development of targeted therapies.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.