Targeting ataxia-telangiectasia (A-T) functional deficiencies using precision medicine approaches

A significant decrease in function of one of the largest proteins known to serve as a ‘guardian’ of the human genome’s integrity, ATM, causes highly debilitating progressive mobility loss across many muscle groups in the body (ataxia-telangiectasia).

We are working on developing novel precision medicines based on small fragments of DNA, antisense oligos (ASOs), to boost the function of the ATM gene in patients by targeting the known and novel aspects of this gene biology. Some of the medicines will be precisely targeting the gene but might be of great benefit to a wide array of patients suffering partial or even complete loss of the ATM gene function.

Most ataxia-telangiectasia patients carry mutations in both alleles of the ATM gene (encoding for one of the largest protein kinases, performing genome integrity surveillance and regulation of mitochondrial redox homeostasis functions), with their cells having varying amounts of mRNA, protein, and ATM kinase activity.

Identification of the best strategies for ameliorating these deficiencies depends on the specific nature of underlying mutations, but in many cases at least one of the alleles leads to the production of some active ATM protein. This suggests that increasing mRNA and/or protein levels produced from the ‘weaker’ hypomorphic (producing a protein with at least some function) or both alleles could become a feasible treatment strategy.

Highly specific and chemically stable, antisense oligonucleotides (ASOs) have become one the most promising forms of precision medicine in the last decade, and have been recently used for upregulation of gene expression or restoration of normal splicing patterns.

We work on developing and testing several novel approaches that will allow the use of ASOs for the upregulation of persisting ATM transcripts in A-T patients, acting via a range of modulational modalities. We are also investigating and using a number of efficient modalities of delivering ASOs to patient’s neurons.