How VY-HTT01 works
Huntington’s disease is a neurodegenerative disorder, caused by mutations in the huntingtin (HTT) gene. The mutation results in the production of an abnormally large HTT protein that accumulates inside nerve cells, causing their death. The loss of nerve cells leads to a progressive decline in thinking and movement ability, as well as behavioral changes and psychiatric disturbances in patients.
VY-HTT01 is a type of gene silencing therapy aimed at addressing the underlying cause of the disease by significantly reducing the amount of damaging HTT protein produced. To do this, VY-HTT01 uses an inbuilt “RNA interference” (RNAi) system.
Genes contain the instructions to make proteins. They are located inside the cell nucleus, but the protein-making machinery of the cell is found outside the nucleus. Therefore, to produce a protein, a temporary copy of the instructions must be produced. This is called a messenger RNA or mRNA. The mRNA is transported outside the nucleus, where the protein can be made.
The RNAi pathway regulates protein production by targeting and removing specific mRNAs. It uses small pieces of RNA called microRNAs (miRNA) that match and bind to the target mRNA to mark it for destruction, preventing more protein from being made.
VY-HTT01 consists of an adeno-associated viral (AAV) vector, a modified virus that can deliver genetic material into brain cells, containing a promotor and miRNA transgene against the HTT mRNA.
Once VY-HTT01 is in the targeted brain cells, the miRNA is produced. This will target the HTT mRNA, and reduce the levels of HTT protein being produced. With less toxic HTT, nerve cell death should be reduced, which could prevent the progression of Huntington’s disease.
VY-HTT01 in clinical trials
VY-HTT01 has not yet been tested in human clinical trials. However, preclinical studies in animal models have produced positive results. Further experiments are also underway.
Sanofi-Genzyme carried out preclinical studies in a mouse model of Huntington’s disease. Results, published in the scientific journal Human Gene Therapy, confirmed that the AAV vector reached the majority of cells in the mouse brain, and the miRNA transgene successfully reduced levels of HTT. Furthermore, the treatment was not associated with any toxic side effects in the mice.
Results of another study, published in Molecular Therapy: Methods & Clinical Development, demonstrated that the AAV vectors are able to both target the relevant areas in the brain of a non-human primate and activate a transgene. This supports the potential effectiveness of VY-HTT01 as a treatment for Huntington’s disease.
Voyager intends to submit an investigational new drug application to the U.S. Food and Drug Administration for VY-HTT01 in 2018, in order to begin Phase 1 clinical trials in Huntington’s disease patients.
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