From the Gene to the Clinic
Khaoula Ben Haj Frej
Dr. Douglas Macdonald ’89
Who wouldn’t want to be able to find the cure for Huntington’s Disease? Dr. Douglas Macdonald, a Trinity alum, is a research who claims to be on the road towards realizing this goal. In his lecture “From the Gene to the Clinic,” he began by showing images of a brain with and without Huntington’s disease, showing a loss of brain tissue with the progression of the disease. While everyone loses brain matter with the years, brain neurons are lost at a much faster rate in patients. He related his studies and general neuroscience to the subject of Michelangelo’s Sistine Chapel, where a figure encased in what seems to be a brain bestows knowledge on a man directly below him.
According to the speaker, Huntington’s disease is an inheritable neurodegenerative and peripheral disease rampant in families, as only a single chromosome with the disease is needed to have it. Neurodegenerative diseases involve the loss of “specific neural populations”(Sajuan and Bates, 2015); according to Dr. Macdonald, this loss is characterized by increased ventricular space in people with Huntington’s Disease. Furthermore, regions in the brain affected by neuon degeneration are parts of the corpus striatum, cortical pyramd, motor, frontal, and occipital cortices, and the hypothalamus (Sanjuan and Bates, 2015). The disease is also late onset, impacting those in their early 40’s, so those who have it have often already had children who have a 50% chance of also having the disease, discovered serendipitous. In fact, it is rampant in Lake Maracaibo, in Venezuela, where thousands of people have the disease. Detecting the disease, often by detecting the protein to which it is attributed, can be incredibly difficult to diagnose in vivo (Chase, 2015). Dr. Macdonald suggests a “disease modification” approach to fight the disease (Sanjuan and Bates, 2015).
Some challenges of this research, includes questions like “What to target” so that knockdown is sufficient, “where to treat” in the brain, “How much to suppress” so that minimum suppression can occur, and finally “when to treat” for optimal results. The answer to that last question is probably, “as early as possible.” Today, there are no curing therapies for Huntington’s disease. Currently, many therapies are symptomatic intervention, attempting to reduce or cure symptoms. Others are disease modifying, where the disease is treated very early on, delaying the onset of symptoms.
Dr. Macdonald’s research is currently attempting to combine pharmacology and therapy that cure the disease itself. The cause of the disease is known; all that is left is preventing its onset. From the gene to the protein, you can intervene at different steps, like transcription, translation, and clearance. Current, pharmaceutical and biotechnology companies work with the clinic to lower or suppress Huntington’s gene expression in brains with the disease. So far, HTT ASO’s have shown reversal and sustained beneficial effects in BACHD mice, or those with the disease. When it comes to drugs, the location of the drug’s introduction is incredibly important. For example, in the NHP striatum in the brain, AAV2-HD5 can lower Huntington protein, reducing expression in that area. Thus Huntington’s was knocked down, without also killing the neurons. Right now, PET tracers are also being considered as biomarkers for the disease, thanks to clinical data with mice.