LHON Opportunity 2
Model systems are the backbone of an efficient and productive therapeutics pipeline. Cell and animal models, organoids, and human tissues each contribute something unique along the path from basic discovery through preclinical development. Perturbation experiments in models can demonstrate how mutations and other genetic variations or secondary factors impact biochemistry and drive pathogenic mechanisms. Such experiments lead to a better understanding of the disease and make it possible to figure out how to counteract disease mechanisms to prevent, treat, or reverse a disease process and—further down the path—to assess safety and efficacy of experimental therapeutics. However, there is consensus among academic investigators and drug developers that more and better-suited models are needed, including those derived from human eyes and retinas, to support an efficient and productive end-to-end research and development therapeutics pipeline for LHON.
LHON Collective can play a pivotal role in supporting a global disease model research network to catalog and characterize existing in vitro and in vivo models and develop and validate new models of LHON. New models would cover more mutations and types of genetic variation and expand available model systems, e.g., zebrafish, organoids, in silico models, and ex vivo models.
The goal would be to establish a core set of well-characterized and validated LHON models that recapitulate all key aspects of the disease, including bilateral loss of vision, variable penetrance, and male preponderance. Models would be made openly available to the research and drug development communities to support mechanistic and translational research.
A disease model research network will be able to determine the strengths, opportunities, and needs for models to support a productive therapeutic pipeline and ensure the core set of models are representative of LHON patients. Development of new models will further support basic discovery, compound screening, mechanism of action studies, and preclinical testing. Achieving these objectives will accelerate therapeutic discovery and development by helping identify disease mechanisms, drug targets, and biomarkers, and enabling rapid testing of hypotheses and validation of early discoveries and experimental therapeutics across a variety of systems.
Importantly, a thorough understanding of mechanism of disease and factors that contribute to conversion will pave the way to developing preventative measures. Prevention is a strategy not often pursued by industry but has the potential to revolutionize the patient experience. LHON could serve as a model for prioritizing prevention, given the incomplete penetrance of disease and the potential for recovery seen in some patients.
Approach to Developing a Global Disease Model Network
Creating a comprehensive and reliable set of LHON models requires collaborative efforts within global research networks. Global research networks serve as a conduit for sharing expertise and resources for advancing a disease area. Such networks can take various forms: they may be formal entities with a centralized agenda and distributed work plans or informal collaborations among independent investigators or collaborative working groups with aligned research interests and goals. Participation in these networks offers opportunities to coordinate efforts, share resources, and validate research findings—a particularly vital aspect in model development.
For a LHON model to be useful, first, it must accurately recapitulate one or more clinical or pathological features of LHON, second, the molecular and cellular mechanisms underlying these features must be determined, and only then can a model be validated for use in drug development. Sharing knowledge and resources across a disease model network while moving through these stages can yield significant benefits. It not only reduces costs and accelerates the pace of research but also offers valuable insights into various aspects of the biology of disease.
Based on our evaluation of the LHON field’s readiness for discovery and translation, we recommend funding grants for precompetitive collaboration to serve as the foundation for establishing a global research network dedicated to disease models. A disease model network will meet the critical need for more and better-suited models to support a therapeutic development pipeline. Given the diverse array of models anticipated to be required to faithfully replicate the clinical manifestations and pathological features of LHON, and the varying expertise necessary for their development, a research network is the most streamlined approach.
Through sharing knowledge and expertise, the network will create a core set of validated models that capture disease heterogeneity and meet the needs of investigators doing experimental work from discovery through preclinical development.
The amount of capital required to establish a global disease model network will vary significantly based on the complexity of the model systems involved. Several LHON investigators shared that there are unpublished mouse model(s) that have not yet been shared with the research community during our one-on-one discussions. Based on these reports and the high value of these models for the field, we recommend initially focusing on the characterization and validation of existing mouse models and building out human tissue bank(s), zebrafish, and organoid models, all of which are scalable and amenable to high-throughput screening. Supporting a network of three to four investigators dedicated to model development would significantly benefit the field.
While the amounts awarded may vary, we recommend up to $100,000 per investigator, per year with expectations of model development commensurate with the grant size. To start, we recommend funding three grants per year with 2-year terms corresponding to an annual budget of up to $300,000 and totaling up to $600,000. Eventually, this can build to an optimized grant program that funds four grants per year with 3-year terms, corresponding to an annual budget of $400,000 and totaling $1.2M.
A reasonable timeline to establish a disease model network is on the order of 6 months. Creating a competitive grant process will require assembling a Scientific Advisory Board (SAB) and putting out an open call for grant proposals that will be vetted by peer review and LHON Collective leadership. Model development and characterization will take 2-3 years.
Considerations to Developing a Global Disease Model Network
The long-term vision for a global LHON model research network is a diverse group of researchers that are pursuing the development and validation of a variety of disease models and shares data and findings about those models freely. In addition to providing funding to develop and validate these models, the program should prioritize funding terms that requires sharing and collaboration as well as budget to bring investigators together to foster greater resource and knowledge sharing. Additionally, we recommend prioritizing an advisory committee to provide long-term oversight, direction, and input on the selected projects.
