Precision Mitochondria

The primary goal of the programme is to demonstrate a new capability, not a specific therapy. Success is defined by the galvanising demonstration: the persistent, reproducible expression of a novel gene from engineered mtDNA in a mammalian system. Proposals will be evaluated on their ability to achieve or enable this demonstration, rather than on the clinical utility of the specific gene used.

When selecting a transgene, applicants should consider the following:

Unambiguous validation: The most critical factor is the ability to prove, reproducibly and beyond doubt, that the gene is being expressed from the mitochondrial genome in vivo, and to quantify the efficiency of engineered mtDNA transformation and expression. If a therapeutic gene makes localisation assays difficult or ambiguous (e.g. hard to distinguish from endogenous proteins), a robust reporter or a distinctively novel gene may be a stronger choice. We will note that in many cases, phenotypic recovery is not unambiguous and the mechanism of action behind the clinical successes of, e.g. mitochondrial transplantation, are questioned.

Generalisability: The ideal galvanising demonstration will inspire confidence that the developed toolkits can be applied to a wide range of future use cases, covering a range of genetic payloads and target cell types. The methods are not intended to apply to only
diseased or defective tissues.

Generalisability comes with a trade-off: For example, selecting a gene very similar to endogenous mitochondrial genes might offer a higher probability of compatibility with the mitochondrial environment -- leading to an easier path to the galvanising demonstration, and higher overall chance of "success" – but may fail to convince the community that the tools can handle more complex editing tasks. Conversely, demonstrating success with a gene with "worst case" compatibility (e.g., a hydrophilic protein or pathologically unwieldy mRNA) proves broad utility and might make "success" more impactful, but carries higher technical risk. Likewise, targeting specific cell types represents a more narrow success, but is perhaps easier, than the ability to target a wide range of cell types.

Portfolio approach: We welcome proposals with varying levels of difficulty and different target genes. We may fund multiple approaches—some optimising for high probability of success (proof of principle) and others for high generalisability (proof of platform). As the programme develops, we expect it to adapt and refocus based on up-to-date learnings and what represents the best chances of success and impact. Ultimately, if the programme succeeds in creating a robust toolkit for mitochondrial engineering, we expect traditional funding bodies and commercial partners to drive the development of specific clinical therapies. ARIA’s role is to break the technical barrier that currently makes those therapies impossible.

No, your end-to-end proposal is not at a disadvantage. We encourage full proposals that recognise technologies (either existing/proprietary or to be developed) that can be of use across the programme. Please be clear in your proposal that you are able and interested in being a technology partner even if we do not choose to fund your end-to-end project, as, in general, we may offer to fund only parts of any given proposal.

Project-level validation and benchmarking are appropriate within TAs 1-4 to the extent that they contribute to achieving successful and useful outcomes in these TAs and/or towards integrating these outputs to serve the galvanising demonstration. Please do not worry about encroaching on the potential scope of ST&R. As we said in the call document, "you should call out platforms, models, methods, and assays that could accelerate progress, improve comparability, robustness, and replication of results, or be used programme-wide to achieve the integrated, galvanising demonstration," and this certainly could apply to project-level validation and benchmarking activities.