LHON Opportunity 3
Basic discovery (e.g., mechanisms of pathogenesis) and drug repurposing research have complementary roles to play in the drug discovery process. Mechanistic research provides the foundational knowledge for identifying key molecular pathways that drive disease and/or promote resilience and may point to biomarkers and drug targets, inform therapeutic strategies, and contribute to our understanding of other mitochondrial diseases or forms of neurodegeneration. Mechanistic knowledge can also be used in drug repurposing to select compound libraries and the most appropriate screening assays to conduct high-throughput small molecule screens. These screens use disease models, e.g., fibroblasts or zebrafish, biochemical assays, and computational methods to systematically identify existing small molecule compounds for activity against the mechanisms that drive disease.
While investigators know what is happening to cause vision loss in LHON, the underlying mechanisms of how and why it is happening have not been discovered yet. During the LHON Scientific Retreat, the field acknowledged many gaps in mechanistic understanding, including those related to:
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Retinal ganglion cell (RGC) structure and function and the contribution of their microenvironment to health and disease ​
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Mechanisms of RGC cell death ​
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Mitobiogenesis and mitophagy ​
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Inflammation
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Neuroprotection ​
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Identification of biomarkers (risk of conversion, disease progression, target discovery, treatment efficacy, recovery)
LHON Collective can play a key role in supporting foundational basic discovery and drug repurposing research. This funding will create a collaborative, interdisciplinary research ecosystem where investigators are focused on the most critical early discovery knowledge gaps in the field. The goal would be catalyzing a productive and diversified therapeutic pipeline that offers more and better treatment options to prevent, halt, and reverse vision loss in LHON patients by creating a research network dedicated to unraveling the complex biological mechanisms underlying disease and identifying drug targets and potential drug candidates more efficiently. In addition to predicting what will work, such a knowledgebase will contribute to understanding translational failures putting a cycle of continuous improvement in motion.
Our funding analysis demonstrated that government funding for LHON research outside of gene therapy is limited and small one-off grants from foundations have not been sufficient to fill the gaps. This was confirmed as we heard from investigators around the world that a major barrier to progress in LHON research is access to sufficient and sustained funding. Developing a strategic funding mechanism to support foundational research and drug repurposing sets the stage for data-driven therapeutic discovery and expedited translation. Achieving this objective will create an efficiency loop where mechanistic research informs high-throughput drug screening, and drug candidates identified by high-throughput screens can be validated by and inform mechanistic studies.
Approach to developing a funding mechanism
Basic science and interdisciplinary collaboration are often what lead to breakthroughs and paradigm shifts in a field—getting there requires reliable funding. We outline a funding approach that would foster interdisciplinary collaboration and commitment to shared goals to advance foundational research and drive therapeutic development.
Research Consortium
Grant programs allow for complete assessment of the capabilities of a team and vetting and refinement of project ideas. Additionally, they are an effective way to identify the most suitable members to build a focused research consortium. A research consortium is a formalized collaboration built on a shared set of research objectives and goals. Members of a consortium can be individuals, institutions, and government or industry stakeholders. Consortia are beneficial to researchers because they provide opportunities to collaborate with people and institutions that may otherwise be outside their own professional networks. For funders, especially those with a research agenda, consortia are beneficial because the framework fosters cooperation across diverse stakeholders to promote speed and efficiency, and an opportunity to set and enforce data collection and sharing standards. Consortia can also provide training, skill building, and mentorship opportunities to young investigators to increase capacity and build a talent pipeline within the field.
Grantmakers intending to build a consortium can choose to open applications to all investigators and institutions or to restrict eligibility to a pre-selected applicant pool. An open application will naturally be more competitive and attract applicants with a diversity of experiences and scientific backgrounds who may bring innovative ideas to the field. A targeted solicitation should be used when it is clear that there are leaders in the field that are most appropriate for the program’s priorities. Investigators awarded grants in this framework will be required to abide by data collection and sharing standards and participate in the consortium to contribute to and benefit from knowledge and resource sharing.
Based on our evaluation of the LHON field’s readiness for discovery and translation, a grant-based research consortium will meet the critical need for funding to support basic discovery, address the many gaps in mechanistic knowledge, and build a collaborative, interdisciplinary research ecosystem to catalyze drug discovery and repurposing research. Most grants provide two to five years of funding, depending on the goals of the program. Considerations for building a grant-based research consortium include:
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Scientific scope and applicant eligibility
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Scientific advisory board and strategic management
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Scientific review and selection process
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Community building within the funded investigator cohort
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Partnerships and agreements to support translation
The amount of capital required to support a grant program varies depending on the scientific scope, duration, and number of grantees awarded per cycle. Awarding five grants would be impactful for the field with the possibility to scale over time based on the evolving research landscape and patient needs. The amounts awarded may vary. We recommend $150,000 per grant, per year, over three years. This corresponds to an initial annual program budget of $750,000. In addition to direct grant funding, budgetary considerations should include compensation for an SAB (ranging from $2,000 - $5,000 per person, per year, depending on their engagement and scope of the program), peer reviewers (typically compensated at a rate of $100 per grant reviewed for their service), and an estimated $50,000 for an optional funded investigator meeting.
A grant program could be launched as early as the fall of 2024, following the establishment of an SAB that will work with LHON Collective to set the scope and refine the scientific strategy. If launched in the fall, we would expect funded research projects to commence in Q3 of 2025.
Considerations
We recommend taking a grant-based research consortium approach for LHON because the field has historically been small and self-contained. A consortium offers a way to integrate new investigators, ideas, and technologies, fostering innovation and expanding the research community’s capabilities. Using a grant program to build the consortium enables investigator-led projects to drive the science while allowing for flexibility and a diversity of approaches in addressing key research questions. As the research landscape evolves and LHON Collective matures, there may be future opportunities to shape projects more directly in alignment with internal scientific strategies.
This is an opportunity to spearhead the development of the first LHON research program. To maximize the impact of this initiative, LHON Collective may want to join forces and networks with one or more other funders, in which case exploring potential partnerships and foundational synergies should happen during the development phase.
It is important to note that basic discovery and drug repurposing research both rely on a variety of model systems. Discovering a drug candidate without appropriate models for validation and preclinical testing will bring development to a stop. Another option would be to collapse the second the third opportunities to create a single consortium with three internal tracks: ​
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Model systems
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Disease mechanisms
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Drug repurposing
