Antisense oligonucleotide treatment of Ataxia-Telangiectasia IND#144349 IND/IDE April 19, 2024

ABSTRACT A-T is a pediatric neurodegenerative condition caused by recessive mutations in ATM, a gene which encodes a critical element of the cellular DNA damage response. Individuals with A-T suffer from gradual loss of muscle coordination due to progressive cerebellar degeneration, leading to loss of ability to swallow, read, communicate, and ambulate. There are currently no known effective treatments for this severely debilitating condition, and it is typically fatal by young adulthood. Here we study the safety and effectiveness of a novel genetic treatment strategy for ataxia telangiectasia (A-T). Antisense oligonucleotides are 15-25 nucleotide snippets of synthetic RNA-like molecules that distribute broadly in the brain and spinal cord when administered via intrathecal injection. They bind to specific genomic targets via Watson-Crick basepairing, and can be designed to change patterns of gene splicing in therapeutically useful ways. 15% of individuals with A-T have mutations that could be treatable using splice-modulating ASOs. Here, we test the clinical therapeutic utility of atipeksen, a 22 nucleotide ASO designed to correct the impact of ATM c.7865C>T, a recurrent mutation that causes disease by creating an abnormal splice site in ATM exon 53. Atipeksen treatment of cell lines from A-T patients bearing this mutation inhibits use of this abnormal splice site, restoring normal ATM splicing and rescuing normal gene function. The current clinical trial is designed to test the safety and effectiveness of atipeksen in A-T in individuals bearing the ATM c.7865C>T mutation. The goal of this study is to slow A-T associated neurodegeneration, delay the progression of neurologic symptoms of A-T, and improve quality of life, using neurologic disability rating scales, brain imaging, and exploratory biomarkers as outcomes. Results from treated patients will be compared against a control cohort of untreated A-T patients with ATM c.7865C>T. Success will provide an empirical foundation for advancing additional precision genetic therapies for A-T and other neurodegenerative conditions.