Preventing Repeat Expansion Disorders at Their Source
More than 50 known genetic diseases are associated with DNA repeats. Many of these diseases, collectively known as repeat expansion disorders, are caused by nucleotide repeats that occur in various genes throughout the body and expand over time. Examples of repeat expansion disorders include Huntington’s disease, myotonic dystrophy and various spinocerebellar ataxias.
Patients with repeat expansion disorders are born with a certain number of repeats in their DNA. Throughout the patient’s life, the repeats expand and increase in number, which is what drives the disease. A growing body of evidence points to one central pathway underlying repeat expansion disorders: the DNA damage response (DDR) pathway. Modifying this pathway therefore holds promise to treat a wide array of repeat expansion disorders at their source.
The Science Behind Repeat Expansion Disorders
A robust body of human genetic evidence, including genome-wide association studies and analysis of human single variants, has identified certain proteins within the DDR pathway that drive repeat expansion.
Our approach selectively knocks down the RNA that encodes those proteins while leaving the underlying DNA repair mechanism intact.
Repeat expansion disorders are genetic disorders associated with expanded DNA nucleotide repeats.
- Genetic data from thousands of patients has revealed that the DNA damage response pathway (DDR) drives DNA repeat expansion, and that number of DNA repeats is associated with disease onset and progression.
- More than 50 of these disorders have been identified, most of which are severe with limited treatment options.
DNA damage response (DDR) proteins drive repeat expansion.
- DDR proteins are important cellular gatekeepers; however, when they encounter certain long DNA repeat hairpins, DDR proteins can drive repeat expansion.
- Expanded DNA repeats are associated with disease onset and progression across multiple repeat expansion disorders.
Triplet is targeting specific DDR proteins with ASOs and siRNAs to stop repeat expansion.
- Triplet is developing antisense oligonucleotides and small interfering RNAs to partially knock down the expression of the DDR proteins involved in repeat expansion.
- Partial knockdown of these proteins prevents malfunction while preserving essential DNA surveillance and repair functions.
Triplet's approach is designed to halt disease onset and progression by precisely reducing activity of select DDR mechanisms.
- The approach is applicable across a wide range of diseases, including Huntington’s disease, myotonic dystrophy and select spinocerebellar ataxias.
Our approach is to precisely reduce the expression of select DDR genes leveraging two well-validated therapeutic modalities: antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). These approaches are tailored to inactivate only the elements of the DDR pathway that drive expansion, while leaving intact DNA repair mechanisms.
Triplet’s development candidates operate upstream of today’s leading approaches. Current approaches achieve only partial reduction in levels of toxic RNA or protein, while leaving DNA repeat expansion unchecked. The DNA repeats therefore continue to expand and increase in toxicity. By contrast, Triplet’s technology prevents repeat expansion at its source.
A growing number of diseases driven by repeated nucleotide sequences have been identified, and most of these diseases are severe and have limited to no treatment options.
Triplet’s initial areas of focus will be repeat expansion disorders with high unmet medical need and robust genetic characterization: Huntington’s disease, myotonic dystrophy and select spinocerebellar ataxias.
We have initiated natural history studies to better understand disease trajectories and establish novel biomarkers. These studies will inform our clinical development plan which will subsequently leverage both established and novel biomarkers, in addition to clinical measures, to monitor the impact of our development candidates on disease progression.
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset. Cell. 2019;178(4):887–900.e14. doi:10.1016/j.cell.2019.06.036
Ciosi M, Maxwell A, Cumming SA, et al. A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine. 2019; 48: 568–580. doi:10.1016/j.ebiom.2019.09.020