Methods and compositions for treating ataxia telangiectasia

Background

Ataxia telangiectasia (A-T) is an incurable autosomal recessive disease that occurs in 1 in 40,000 to 100,000 people worldwide. It is caused by mutations in the Ataxia Telangiectasia Mutated (ATM) gene. A-T is characterized by neurodegeneration in the central nervous system, immune deficiency, and skin and ocular telangiectasias (i.e., small, dilated blood vessels). Individuals with A-T may have mobility issues by age two that may require the use of a wheelchair by age 10. They are also prone to chronic lung infections and are at an increased risk of cancer, most frequently acute lymphocytic leukemia or lymphoma. The life expectancy of patients with A-T is approximately 25 years and there is no cure for A-T or way to slow its progression. Current treatments are symptomatic and supportive such as physical therapy to help maintain flexibility and speech therapy to teach children how to control breathing.  

Technology Overview

Dr. Timothy Yu’s group has designed several antisense oligonucleotides (ASOs) that restore wild-type splicing of an ATM gene comprising two mutations associated with A-T and that could be used to treat A-T. These ASOs are designed specifically to treat A-T due to two mutations, one that is found in 18% of patients with A-T in the United Kingdom (ATM(NM_000051.3):c.5762ins137), and one mutation that is found in up to 5% of patients with A-T in Turkey (ATM(NM_000051.3):c.7865C>T). In a cell model of A-T comprised of cultured fibroblasts from a patient with the ATM(NM_000051.3):c.5762ins137 mutation, Dr. Yu’s group demonstrated normal splicing in more than 50% of the cells after they were transfected with an ASO. One of the ASOs, AT043, resulted in greater than 70% normal splicing. Additionally, the inventors designed ASOs that blocked abnormal splicing induced by the ATM(NM_000051.3):c.7865C>T mutation, with one candidate, AT008, promoting recovery of up to 50% normal splicing in the A-T cell model.

Applications

• Development of a therapeutic for the treatment of ataxia telangiectasia

Benefits

• The technology would provide a treatment for ataxia telangiectasia, an incurable disease that has no current treatment or method to slow its progression