Genetic Elimination of the Protein Huntingtin, to cure Huntington’s disease

Jun, 2021 - By WMR

A recent research on Huntington’s disease focused on eliminating the toxic effect of this mutant Huntingtin protein.

Huntington’s disease (HD) is a rare inherited genetic disorder that cause progressive degeneration of the nerve cell in the brain. The disease is characterized by a mutation of the HTT gene, responsible for the production of the protein Huntingtin. Although exact mechanism of the protein function is not known clearly. However, it appears that this protein has an important role in regulation of the neuron hence controlling the function of the Central Nervous System (CNS).

Human DNA has got many repeat sequences characterizing vital species functions. HTT gene, contains a DNA segment, also known as CAG Trinucleotide repeat sequence. In a normal HTT gene, this CAG repeat for about 10 to 35 times. People diagnosed with HD, is seen to have 40 or more repeats with a borderline of 36 to 39 repeats, showing borderline disease occurrence capabilities.

Researchers of the Buck Institute’s Ellerby lab, recently targeted a protein, FK506-binding protein 51 or FKBP51 that promotes the clearance of these toxic proteins involving the mechanism of autophagy. FKBP51 induced autophagy could also remove the toxic effects that is associated with an immune-suppressing drug called as rapamycin. The result showed both rapamycin and FKBP51 inhibitor, SAFit2 can control the HD neurons. The inhibitor, SAFit2 crosses the blood-brain barrier to activate mTOR-independent pathway, which in turn starts the autophagic mechanism for the clearance of the toxic mutant protein. This study was conducted on the mice as well as human stem cell model.

We already know that FKBP51 get dysregulated while a body approaches senescence. The protein is also associated with other problems like Parkinson’s disease, Alzhiemer’s, schizophrenia and other different post-traumatic disorder. An anti-sense oligonucleotide (ASO) designed drug were given in the model organism for silencing the gene required for HD, which was injected in the fluid-filled region of spinal cord and brain. Although, the experiment failed as the drug was unable to reach the peripheral tissues of the CNS. Optimism is shown by the researchers that encircles different types of pre-clinical trials for curing the disease.