Stem cells and HD drug discovery

Last week, CHDI hosted a stem cell meeting in Princeton, NJ, chaired by Thomas Vogt (CHDI’s new VP for Discovery & Systems Biology), and myself. We hosted several eminent scientists working on the use of stem cells for understanding HD pathogenesis, and identifying new mechanisms for potential therapeutic treatments. The meeting did not cover the use of stem cells as therapeutics themselves, or the approach to treat brain disorders by stimulating endogenous stem cell/progenitor cell proliferation or differentiation. This will be the subject of another meeting in the future.

As people might know, stem cells are cells that have the capacity to both self-generate, as well as generate multiple cell fates; that is, we can use stem cells derived from HD as well as unaffected subjects, to generate the cell types most vulnerable in HD… this typically means we want to work with human cells derived from people carrying the HD mutation, so that we can study, and manipulate, human biology. The cells that -at the moment- we care about the most are cells that form part of the region of the brain that degenerates in HD: medium spiny (or also called projection) neurons of the striatum, cortical projection cells (the cells that originate in deep cortical layers and which innervate the cells of the striatum), and glial cells. All of these are affected in HD: we know they display pathology, and in rodent models of HD, we can identify abnormalities pretty much as early as we can identify any problems with those animal models of HD.

What we are struggling with is why those cells are dysfunctional when mutant HTT is expressed, and what are the critical mechanisms that lead from the mutation to their dysfunction. We also struggle with the fact that all of the mouse models of HD which display signs of disease contain mutations in HTT that bear a very large (juvenile range or superphysiological ranges) CAG expansion. So we need to understand whether the pathogenic and molecular mechanisms that apply to the ‘normal pathogenic range of CAG expansions’ in humans, are similar to what we see in rodents. We think that the use of patient derived stem cells will help us in this regard.

One challenge in the field has been to generate the relevant cell types in vitro, so that we can study how their biology is affected by HTT mutations. CHDI has been funding, alone or in concert with NINDS, the development of methods to generate these cell types, and there has been great progress in this regard. Multiple teams reported on their efforts to generate cortical and striatal cells, and also reported on identifying phenotypes in the HD cells. What this means is that we now have a (limited but useful) understanding that in normal CAG HD cells, we can uncover alterations in culture. the initial findings suggest that there is a CAG-length dependency of the cellular alterations discovered. But we still need to extend these initial studies to many more cell lines. After all, not all patients show the same symptoms of the disease (we are all different) so we need to ensure we analyze multiple cells derived from a collection of people at risk or suffering the disease. This is where the long-term efforts of CHDI and the medical community will help: since through Enroll-HD, TRACK, Predict, and other studies, we have been following the progression of many patients or subjects at risk for HD, we have a rich clinical history. This will allow us to select (with their consent and participation of course!!) the subjects from whom cells might be derived, and studied. This type of work will allow us to establish very important correlations between the clinical progression of HD, with the consequences of the mutation in a cellular context. We will continue to strive for alignment and cooperation within the field, which will be needed to ensure this approach matures to a level where we can identify the critical mechanisms that translate the mutation to a clinical phenotype. It is these mechanisms that we must target, and correct (or eliminate) so that we can treat HD more effectively.

 Time will tell whether the phenotypes identified using stem cells thus far will lead us in new directions. But what is certain is that now we can seriously start studying the human disease in a much more tractable system. There is reason to be hopeful and excited!