Professor Tanese of the New York University School of Medicine discusses Huntington’s disease
Mutation in the huntingtin gene causes Huntington’s disease, a heritable and fatal neurodegenerative disease. The production of mutant huntingtin (HTT) protein is thought to be responsible for alterations of normal processes that ultimately result in the death of neurons. Thus, the mutation is considered a gain-of-function mutation. The function of normal HTT protein remains elusive. HTT is a large protein whose structure consists of many helical repeat units. This suggests HTT may serve as a platform for many proteins to bind, facilitating integration of multiple biochemical pathways occurring in the cell. Although mutant HTT is expressed early in life, most patients develop symptoms in mid-life. Strikingly, advanced imaging studies of the brain of pre-symptomatic patients have revealed shrinking of certain brain regions. This suggests that changes triggered by mutant HTT are already occurring at the molecular level early in patient’s life. The affected brain compensates for the loss of neurons until mid-life when compensatory mechanisms begin to fail, giving rise to various symptoms of the disease. Mutant HTT is expressed throughout the body. Why neurons are most sensitive and die from toxic effects of mutant HTT remains unclear.
The role of normal HTT
Normal HTT is essential for life. Mice engineered to have the HTT gene removed die early in development prior to birth. This finding prompted researchers to ask whether the role of HTT in embryonic development may be linked to the pathogenesis of Huntington’s disease. In other words, there may be a loss-of-function component to the disease in addition to the gain-of-function attributed to mutant HTT. To explore this idea researchers generated mice that expressed very low levels of normal HTT for a defined period of time very early in life. Although normal levels of HTT were restored after a short period of low HTT expression, the adult brain showed signs of neurodegeneration. The results suggest that loss of normal HTT sets a stage for increased vulnerability to toxic effects of mutant HTT later in life. Interestingly, removal of HTT in the brain of adult mice does not seem to have measureable effects. These experiments have important implications for the design of therapeutics to treat Huntington’s disease.
Lowering mutant HTT
Animal studies so far have shown that lowering mutant HTT is the most effective approach to delaying or reversing symptoms of Huntington’s disease. There are several ways to lower the expression of mutant HTT. However, selective lowering of mutant HTT without affecting normal HTT is difficult to achieve. This is because the mutant gene is very similar to the normal gene and therapeutic agents cannot distinguish between the two genes thus targeting both. If loss of normal HTT in the adult brain has a minimal effect as mentioned above, lowering both mutant and normal HTT expression may still be beneficial. This has been demonstrated in mouse models of Huntington’s disease. However, further studies need be conducted to determine consequences of lowering normal HTT expression in the adult brain.
The era of precision medicine has opened doors for correcting many genetic diseases. Huntington’s disease is no exception. Removal of excess repeat sequences from the mutant HTT gene has been achieved in laboratory settings. This approach will preserve the levels of normal HTT. Many challenges lie ahead to bring the new gene editing technology to bear. Researchers are committed to pushing the boundaries in order to find treatments and cures for this terrible disease.