Huntington disease is a fatal and inherited neurodegenerative disease. It is characterized by diminished voluntary motor control, cognitive decline and psychiatric disturbance. Symptoms of the disease first appear in the thirties to fifites, with death usually occurring 15 to 20 years later. While there are still no effective therapies for this disease, recent research discoveries have provided insight into how the disease develops. The normal huntingtin gene encodes a protein that is important for neuronal health. Although everyone has two copies of the huntingtin gene, people with Huntington disease have one normal copy and one mutated copy. When a person has a mutated version the gene, the huntingtin protein accumulates within cells and engages in a variety of aberrant interactions that cause disease symptoms.
Dr. Amber Southwell is working to develop a strategy for turning off the mutant copy of a patient's huntingtin gene in order to prevent or delay the onset of the disease. Her lab has identified genetic characteristics that are more common in mutant than in normal huntingtin genes and have generated therapeutic reagents that specifically target these mutant variations. This effectively switches off the mutant but not the normal gene in cellular models of Huntington disease and results in the selective reduction of the mutant huntingtin protein.
Dr. Southwell will test the efficacy of these candidate therapeutics by measuring their ability to reduce the level of the mutant but not the normal protein in the living brains of a mouse model of Huntington disease. She will also evaluate how the therapeutic reagents influence the behavior and brain pathology of these mice. This targeted approach of selectively silencing the mutant gene while sparing the normal gene is preferable to other approaches that prevent the expression of any huntingtin protein. The normal huntingtin protein is important for neuronal health, and long-term reduction of this protein may not be well tolerated. Hopefully this targeted approach will lead to new therapies to prevent or delay Huntington disease onset.