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Yaya Foundation for 4H Leukodystrophy meeting summary notes

Inaugural #4HLCN Working Meeting Summary

November 9 – 10, 2020

4H Leukodystrophy Collaboration Network Background

In 2020 the Yaya Foundation thoughtfully assembled and launched the 4H Leukodystrophy Collaboration Network, or #4HLCN, which comprises the world’s foremost experts in 4H as well as other experts in gene and cell therapy, proteomics, organoids and other fields of critical importance to the development of 4H therapeutics. Guided by our research director and scientific advisors, our goal is to work together to accelerate and advance therapy discovery.

Working Meeting Focus & Format

On November 9 – 10th, the inaugural #4HLCN meeting brought together patient representatives, investigators and their students from five North American and European countries, and the Yaya Foundation’s advisors, representing the academy, biotech industry and venture capital. The esteemed and diverse group illuminated many facets of 4H:

  • parents provided first-hand experience of the day-to-day life with 4H;
  • clinicians shared what is known about 4H and the current state of clinical investigation;
  • scientists presented the most recent findings on basic and applied research; and
  • our advisors used their expertise in therapy development to keep the focus on the fastest and most direct path towards our goal: treatments that will improve and lengthen the lives of people affected by 4H, and a cure.

The first day of the #4HLCN working meeting was dedicated to taking stock and sharing knowledge of 4H.

Three families shared what it means to be a parent of a child with 4HL: their diagnosis and journey, the challenges of providing care, the crushing emotional burden, and also how they rally support and find joy in the resilience of their children.

Presentations summarizing clinical findings and pathogenesis of 4H emphasized the breadth of the clinical spectrum and the gaps in understanding the molecular and cellular pathology. Gene replacement therapy and cell therapy could be two potential avenues towards a cure for 4H. Both of these strategies have been pursued for other leukodystrophies / CNS disorders and studies in relevant model systems as well as promising results from human trials were presented. We discussed how to apply the learnings from those results to finding a cure for 4H.

In the last session of the day we heard about ongoing 4H research projects, including proteomic studies of the RNA polymerase III complex, expression studies in iPSCs and results on animal model systems for 4H.

Based on these learnings, the #4HLCN spent the second day of the working meeting defining the most urgent scientific questions as well as what projects and specific experiments need to be performed to address them. Recurring themes included:

  • natural history studies;
  • biobanks;
  • suitable animal model systems; and
  • biomarker development.

The #4HLCN discussed strategies for short and long-term progress, how to prioritize work, and assembled the basic building blocks for a Roadmap To a Cure.

Working Meeting Key Messages

  • Collaboration and knowledge exchange is key for success.
  • Gene replacement therapy is currently most advanced toward the next milestone – proof of concept – and may progress towards the clinic within a five-year time frame.
  • Cell replacement therapy remains promising, but requires further research.
  • The lack of understanding of the molecular pathology and natural history of 4H are impeding progress; research addressing it is a high priority.