Three letters—CAG—determine whether a person is healthy or develops Huntington’s disease. HD is a progressive brain disorder that affects movement, cognition, and personality. More than 30,000 Americans have HD, and no treatment can slow the disease.
HD stems from a mutation in the huntingtin gene caused by an expanded CAG repeat. People with fewer than 26 repeats remain unaffected. Those with 40 or more will develop the disease. Scientists do not yet know why this expansion causes HD. They suspect the added repeats create a mutant Huntingtin protein that cannot function normally.
Many diseases begin long before symptoms appear. In HD, symptoms surface between ages 30 and 50, but molecular problems start decades earlier. Scientists are creating early‑stage models to study how the disease develops.
HD patient iPSCs with expanded CAG repeats help researchers examine HD’s impact on brain development. In a CIRM‑funded Nature Neuroscience study, the HD iPSC Consortium used these cells to track neurodevelopmental defects.
They analyzed neural cells from HD iPSCs and compared gene activity to healthy cells. RNA‑seq revealed many altered genes involved in neuron formation and maturation. HD neurons also showed structural differences in lab cultures. These results suggest problems with neurodevelopment and adult neurogenesis in HD.
After mapping the disrupted gene networks, the team identified a small molecule, Isx‑9, that targets them and reverses HD‑related defects in neurons. In HD mice, Isx‑9 improved cognition and neurogenesis‑related symptoms.
The authors conclude that HD disrupts gene networks tied to development and neurogenesis. Isx‑9 can restore some functions, suggesting future treatments should target early events.
They also shared additional insights in a short interview with Dr. Leslie Thompson, Dr. Clive Svendsen, and Dr. Steven Finkbeiner.
Q: What is the mission of the HD iPSC Consortium?
To create a resource for the HD community of HD-derived stem cell lines, as well as to tackle problems that would be difficult to do by any lab on its own. Through the diverse expertise represented by the consortium members, we have been able to carry out deep and broad analyses of HD-associated phenotypes [observable characteristics derived from your genome]. The authorship of the paper – the HD iPSC consortium (and of the previous consortium paper in 2012) – reflects this goal of enabling a consortium and giving recognition to the individuals who are part of it.
Q: What is the significance of the findings in your study and what novel insights does it bring to the HD field?
Our data revealed a surprising neurodevelopmental effect of highly expanded repeats on the HD neural cells. A third of the changes reflected alterations in networks that regulate neuronal development and maturation, and when compared to neurodevelopmental pathways in mice, maturation appeared to be impacted. We think the significance is that there may be very early changes in the HD brain that contribute to later vulnerability due to the HD mutation. This is compounded by the inability to mount normal adult neurogenesis or formation of new neurons, which could compensate for the effects of mutant HTT. The genetic mutation is present from birth, and with differentiated iPSCs, we are picking up signals earlier than we expected that may reflect alterations that create increased susceptibility or limited homeostatic reserves, so symptoms do result over time.
What we find encouraging is that using a small molecule that targets the pathways that came out of the analysis, we protected against the impact of the HD mutation, even after differentiation of the cells or in an adult mouse that had had the mutation present throughout its development.
Q: There’s a lot of evidence suggesting defects in neurodevelopment and neurogenesis cause HD. How does your study add to this idea?
Agree completely that there are a number of cell, mouse, and human studies suggesting problems with neurodevelopment and neurogenesis in HD. Our study adds to this by defining specific networks that may be regulating these effects, so drugs can be developed around them. Isx9, which was used to target these pathways specifically, shows that even with these early changes, one can potentially alleviate the effects. In many of the assays, the cells were already through the early neurodevelopmental stages and therefore would have the deficits present. But they could still be rescued.
Q: Has Isx-9 been used previously in cell or animal models of HD or other neurodegenerative diseases? Could it help HD patients who already are symptomatic?
The compound has not been used, to our knowledge, in animal models to treat neurodegeneration, although it was shown to affect neurogenesis and memory in mice. Isx9 was used in a study by Stuart Lipton in Parkinson’s iPSC-derived neurons in one study and it had a protective effect on apoptosis [cell death] in a study by Ryan SD et al., 2013, Cell.
We think this type of compound could help patients who are symptomatic. Isx-9 itself is a fairly pleiotropic drug [having multiple effects], and more research would be needed [to test its safety and efficacy].
Q: Have you treated HD mice with Isx-9 during early development to see whether the molecule improves HD symptoms?
Not yet, but we would like to.
Q: What are your next steps following this study, and do you have plans to translate this research into humans?
We are following up on the research in more mature HD neurons to determine at what stages one can rescue the HD phenotypes in mice. Also, we would need to do pharmacodynamics and other types of assays in preclinical models to assess efficacy and then could envision going into human trials with a better characterized drug. Our goal is to ultimately translate this to human treatments in general and specifically by targeting these altered pathways.
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My daughter decided to be tested for HD after her father developed the disease. Sadly she was to test positive to HD with a high CAG reading!
During the testing, it was discovered that me as her mother had a CAG of 33, showing that my Huntington gene had started to mutate also!
After further investigation, my mother was also shown to have a CAG of 33 however all other family members were in turn all tested and thankfully all had the ‘normal ‘ CAG range!
Thought this would be of interest as your article was to all of us, that eagerly await those all important positive research findings!