Diagnostic, prevention and treatment platform for tandem-repeat expansion diseases.

Important results from the project

The aim has been to develop a unique oligonucleotide therapy (OT) for tandem-repeat disorders, with a focus on Friedreich’s ataxia and Huntington’s disease. These disorders especially affect the nervous system. The underlying mechanism of tandem-repeat diseases is that short pieces of the genetic material, normally 3 nucleotides expand in tandem yielding repeats that have increased several hundred-fold. The repeats cause the disorder, and the mechanism varies among illnesses. We have initiated the development of novel diagnostics and therapy.

Expected long term effects

The project has consisted of 2 parts, 1) to develop novel diagnostics and 2) to develop a new treatment. 1) For the novel diagnostics we have used a technology based on that long sequences of DNA are read by passing them through nanopores, one strand at a time, with sequence variations being detected by changes in an electric current. 2) The new therapeutic method is based on using OT binding directly to chromosomal DNA. The principle differs between Huntington’s Disease where the aim is to downregulate expression, whereas for Friedreich’s Ataxia the expression should be upregulated.

Approach and implementation

For the novel diagnostics, the setup has been to analyze chromosomal DNA without using amplification based on the polymerase-chain reaction (PCR), because PCR often introduces errors in the sequence. Our chemically modified OT binds directly to genomic DNA and can thereby be developed for both therapy and as prevention of tandem-repeat diseases. None of the existing, competing ON strategies can achieve this. Our drug may potentially be able to revolutionize treatment of these rare and complex disorders.