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A repeated stretch of DNA in one gene becomes too long, and the protein it makes gains a new, harmful property that slowly kills brain cells controlling movement, thinking and mood. The genetics could not be clearer: inherit the expansion and you will develop the disease. What is not clear is how to get an editing machine into billions of neurons, spread throughout the brain, behind a barrier evolved specifically to keep things out.
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Huntington's disease is caused by CAG repeat expansion in HTT, producing mutant huntingtin with a toxic gain of function; it is autosomal dominant with essentially complete penetrance above about 40 repeats. Because the pathology is gain-of-function, silencing or removing the mutant allele is the therapeutic goal — ideally allele-selectively, since wild-type huntingtin has essential functions. Delivery across the blood-brain barrier to sufficient neurons remains unsolved, and the fact that neurons do not divide means homology-directed repair is unavailable.
Two hard problems, not one
Delivery is the obvious one. The less obvious one is selectivity: everyone with Huntington's has one normal copy of the gene and one expanded copy, and the normal copy does something important. A treatment that silences both may create a new problem while solving the old one, so allele-selective approaches — targeting variants that happen to sit on the expanded copy — are an active area.
Non-editing approaches to lowering huntingtin have had a difficult clinical history, which has made the whole field appropriately cautious about this target.
Sources
- MedlinePlus Genetics, U.S. National Library of Medicine
Huntington disease ↗