Vanessa Wheeler, PhD

From Genetics to Therapeutics: Targeting Somatic Instability in Repeat Expansion Disorders

Over 50 fatal and untreatable genetic neurological and neuromuscular diseases occur as the result of inheriting an unusually long stretch of repeating letters of the DNA code within a particular gene. This is equivalent to a typographical error or stutter where a word is copied too many times.

A characteristic of these repeat expansion diseases (REDs) is that the culprit DNA sequences progressively increase in length in neurons of the brain as a person ages. Once the repeats reach a certain length, they trigger toxic process(es) that cause the neurons to die.

Our growing understanding of this mechanism across many diseases is game-changing because it indicates that therapies that intervene in repeat lengthening could slow or halt the disease process prior to clinical onset. Further, the same therapies could be used to treat multiple diseases.

I am conducting research into REDs to build fundamental knowledge of the dynamics of repeat mutations and to turn this knowledge into therapeutic strategies. This work will have a significant impact in the development of disease-modifying therapies for a class of devastating and currently intractable genetic diseases.

With the support of the MGH Research Scholar award, I plan to focus my efforts on modifier gene discovery that includes using CRISPR-based manipulations in mice models and human cell systems, variant-to-function studies that leverage human genetic data to dissect the functional impacts of human modifier variants and preclinical studies and therapeutic development.

I am deeply honored to have received the award, which will accelerate our work to inform and refine the next generation of drugs with the promise to treat these devastating neurological diseases at their root.