Oligonucleotide approach to treat exon skipping diseases 

Background

Almost half of mammalian genomes contain repeat DNA sequences known as transposable elements (TE) or transposons. Many transposons have the ability to mobilize and change location in the genome, yet their role in human health and disease is not well defined. RNA transposons (i.e., retrotransposons) move via a copy-and-paste mechanism using RNA as an intermediate. Retrotransposition-mediated events in mammals are known to produce alterations in the brain and are involved in cancers. Current methods for treating the deleterious effects of transposon insertion are required. One such disease involving transposon insertion is Batten Disease, a rare, recessive disorder resulting in the progressive degeneration of the brain and retina. Symptoms of the disorder include blindness, seizures, and motor and cognitive decline.

Technology Overview

Researchers at Boston Children’s Hospital have developed a novel diffusion MRI Dr. Timothy Yu’s research group has developed antisense oligonucleotides (ASOs) for the treatment of diseases and disorders associated with the deleterious effects of transposon insertion. This technology also provides a method of screening for agents that inhibit a splicing event caused by a retrotransposon insertion and provides a method of monitoring treatment progress from candidate ASOs.

The impetus for developing this technology was the identification of a child displaying severe, rapidly progressing neurological decline, progressive cerebellar atrophy, and other clinical features consistent with Batten disease. A series of ASOs were designed, synthesized, and screened, culminating in the selection of a single lead candidate, TY777, later renamed Milasen/TY777. Following extensive consultation with the FDA and dozens of internal and external advisors, Dr. Yu’s team received approval from the FDA to conduct a n-of-1 trial of Milasen on the child. The patient experienced no notable adverse effects and her clinical profile stabilized in many clinical domains after starting treatment, including a significant reduction in seizure activity.

Applications

• Development of antisense oligonucleotides (ASOs) for the treatment of diseases and disorders associated with the deleterious effects of transposon insertion
• A method of screening for agents that inhibit a splicing event caused by a retrotransposon insertion
• A method of monitoring treatment progress in patients treated with an ASO for a condition with transposon insertion

Benefits

• A cure for Batten Disease is not currently available.

Publications

https://www.nejm.org/doi/full/10.1056/nejmoa1813279