CHDI Foundation is exclusively dedicated to collaboratively developing therapeutics that will substantially improve the lives of individuals with Huntington’s disease. Even with this clarity of mission there is a practical limit to the number of initiatives that can be orchestrated in parallel, so CHDI must prioritize where our resources will be most effective in HD drug discovery. This requires a transparent strategic framework that ensures alignment among the various stakeholders, from biology to chemistry, early discovery to translational to clinical, as well as the important integration of CHDI staff with the broader community in the academic, biopharmaceutical, and regulatory sectors.
We have organized our preclinical research programs—which include discovery biology, translational biology, and medicinal chemistry—around the concept of Major Focus Areas (MFAs) to provide such a framework and to better align our scientific strategy and portfolio.
Each MFA circumscribes a particular aspect of HD biology and/or an approach to advancing associated targets, mechanisms, and therapeutic candidates. Informed by the published literature, ongoing discussions with HD research colleagues and their work, our internal programs, and findings in related diseases—particularly other neurodegenerative diseases, proteinopathies, and triplet-expansion disorders—we arrived at a working list of MFAs: HTT Lowering, HTT Structure & Function, Neuronal Dysfunction, Stem Cells & Regenerative Medicine, DNA Repair & Handling, and Unbiased Systems-based Approaches.
We applied three main strategic drivers to select these six initial MFAs for further consideration. First and foremost was the requirement that an MFA had a robust evidence base in HD biology. Second, we sought to highlight MFAs that, to the degree we could predict, were most likely to deliver the therapeutic strategies most meaningful to patients; our intent is to select therapeutic programs that will have the largest effect size and/or disease-modifying potential over those that would be palliative or symptomatic treatments. Third, we wanted to ensure that CHDI could play an effective role in the HD ecosystem by collaboratively enabling others while also driving projects that are of a scope, risk profile, and magnitude that others might not be able or willing to sustain.
The MFA selection process involved the compilation of comprehensive white papers that articulate the evidence for and against that specific area of HD biology, the key unanswered questions, and an experimental strategy to address those open questions over a three-year period. These white papers relied on the existing body of knowledge from the published scientific literature, CHDI internal project reports, and the advice of external investigators with relevant expertise.
These synopses of these comprehensive MFA white papers presented here are intended to give the wider HD research community insight into CHDI’s current focus, share ideas, and prompt further discussion. In the interests of brevity and to avoid any omissions, we decided not to reference any of our collaborators or colleagues in these snapshot reports, but the accomplishments of the wider HD research community are essential to CHDI’s work.
The MFA exercise has already proven fruitful and has led us to make some consequential decisions. After careful review we consider that the existing evidence for the idea that a deficit/defect in energy and metabolism materially contributes to HD pathophysiology is not sufficiently compelling to maintain a major program. We have consequently deprioritized the Energetics & Metabolism MFA and now describe it as one of a number of emerging opportunities. A handful of ongoing energetics projects will now run their course to completion and only small, focused, proof-of-concept projects will be initiated until such time as additional human evidence emerges to change our thinking in this area. Conversely, in light of the recent intriguing findings from genome-wide association studies we have recently established a new DNA Handling & Repair MFA. In this way the white papers serve as a roadmap for our decision making; projects that are well-aligned with the MFA strategies will be resourced and accelerated.
This is not to say that the current MFAs are now the only areas that interest us. CHDI will continue to be receptive to novel ideas and will explore new areas of biology that have relevance to HD, especially when the scientific evidence is promising in humans and a compelling case can be made that approaches a threshold concomitant with that of the MFAs identified so far. This is particularly true as the accomplishments of the HD research community mature into a pipeline of projects entering the clinical phase. The sophistication of HD clinical research has also grown in virtually every aspect, from the underlying mechanistic hypotheses to selection of the candidate interventions, to experimental and statistical design, to the use of well-tailored biomarkers and outcome measures. These observational and experimental medicine studies and interventional trials will provide human data to reinforce the approaches we have taken as a community, or the impetus to nominate new directions as emerging opportunities. We hope that the MFA synopses will give you a better understanding of the rationale behind our strategic selections and some of the proposed areas of investigation.