VDP-139 [Funding] Luminova: mtON gene therapy in the aged eye

One-liner: Rejuvenating mitochondrial function by harnessing the power of light

Notes: Due to Snapshot’s character number limitation, this proposal is an abridged version of the full proposal available on Discourse.

Longevity Dealflow WG team

• Senior Reviewers: Project has been evaluated by 3 academics and 1 biotech executive
• Shepherd: Maria Marinova
• Other squad members: Eleanor Davies, Cassy Le, Adrian Matysek
• Sourced by: Jason Mercurio

Project PI

• Dr Shahaf Peleg

Simple Summary

Luminova Biotech holds exclusive rights to mtON technology, enabling mammalian cells to convert light energy into chemical energy, thus generating ATP independently of oxidative phosphorylation. This technology has improved lifespan and health in C. elegans and is effective in human and mouse cells. It offers promising applications, particularly in treating age-related human vision loss, representing a significant advancement in treating internal organs.

Problem

Older individuals suffer from age-associated vision loss and an increased prevalence of metabolic diseases, such as diabetes, which together impair eye function. Specifically, reduced oxygen transport, mitochondrial dysfunction, and accumulation of lipofuscin are involved in vision loss with aging and related maladies. Full proposal on Discourse.

Solution

The core of Luminova’s solution is mtON technology, a novel and disruptive approach. mtON is an engineered, light-activated proton pump localized to metazoan mitochondria. This technology is designed to power mitochondrial function independently of metabolism and oxygen. Full proposal on Discourse.

Opportunity

The projected longevity market is estimated to reach $270 billion by 2024, driven by a growing population experiencing vision loss. Currently, over 300 million people suffer from moderate to severe vision impairment, a number expected to increase by 50% over the next 25 years. Full proposal on Discourse.

Experimental plan and budget

MILESTONE 1: Assess the bio-distribution of mtON in the mouse eye

The team will use AAV2/9 and use two methods of injections of AVV-mtON in the eye. The team will then observe the type of cells that express mtON and confirm its mitochondrial localization. Next, the team will proceed with in vivo assessment of mtON activity functionality of mtON in isolated mitochondria. Finally, the team will determine the optimal dosage of the AVV for the next steps.

MILESTONE 2 – Assess the therapeutic benefit of mtON in the mouse eye A) The team will test if mtON attenuates age-associated vision loss. The team will first inject AAV-mtON to the eye of old mice and test whether neuronal activity and metabolic rates of retinal cells are improved, along with vision. In parallel, the team will inject AVV-mtON in 8 months old mice to test a preventive approach and follow up with the mice until they reach old age. B) In parallel, the team will employ a diabetic retinopathy mouse model by injecting STZ to mice. Diabetic retinopathy is characterized by a hypoxic environment, mitochondrial dysfunction, and an accumulation of toxic byproducts and mtON treatment is an ideal gene therapy. Collectively, this proposal will allow the team to conduct a thorough pre-clinical trial in mice that will provide a suitable basis to move forward towards clinical trials in humans. This will also be the first critical step to translating mtON technology into humans – not only to treat aging, but to eventually explore the potential for enhancing human longevity through the integration of partially solar-powered mechanisms.

Pending successful results, we will seek funding to continue clinical trials in a timely manner.

Budget

$140,000 for two years

VitaDAO Funding Terms

This project will be funded via a Joint Development Agreement, to collaboratively develop a project. Luminova retains ownership of the intellectual property, while using IP-NFT and IPT technology for project management and governance. Based on funding amounts for this joint development project ($140,000 VitaDAO and Luminova $30,000), IPT initial distribution would be: Luminova: 17.65% and VitaDAO 82.35%. Luminova will pay non-Luminova IPT holders 5% of proceeds. Funding, profits, and decision-making processes are shared, with a condition of Luminova regaining full control of the project when a 5 million seed round is raised. Finer details will be ironed out in ongoing negotiation.

1. Timeline

Relevance to Longevity

The project focuses on combating age-related vision loss. Successfully treating this condition promises to significantly improve life quality for the elderly.

The project's ambitions aim to demonstrate that the treatment, starting with the eye, could be an approach to slow down or reverse aging in the entire body.

The project covers the fundamental challenges of aging: cellular senescence, mitochondrial dysfunction, accumulation of toxic waste, and systemic vascular decline.

Team

Dr. Shahaf Peleg, Project Lead

• PhD Georg-August-Universität Göttingen 2010; BSc Ben Gurion University, Beer Sheva 2006
• Tenured Group Leader at the Research-Institute for Farm Animal Biology (FBN), Dummerstof, Germany
• Luminova Biotech, CEO

Dr. Andrew Wojtovich

• Assoc. Prof. Department of Anesthesiology and Perioperative Medicine (SMD)
• Assoc. Prof. Department of Pharmacology and Physiology (SMD), University of Rochester
• Luminova Biotech, CSO

Peter Hungerford

• Luminova Biotech, CFO

Strengths

Innovative Approach: Luminova's focuses on rejuvenating mitochondrial function through the groundbreaking use of optogenetics.

Exclusive Technology: Luminova Biotech holds exclusive rights to mtON technology, a light-activated proton pump engineered to enhance mitochondrial function independently of oxidative phosphorylation.

Strategic Target: Focusing on mitochondrial membrane potential as a target is strategic, given its central role in aging.

Application to Aging Phenotype: The project aims to improve the aging phenotype by targeting age-related vision loss as an early-stage proxy.

Ambitious Long-Term Vision: Luminova's long-term vision involves upgrading mtON for functionality in inner organs, with the ambitious goal of whole-body mtON gene therapy to increase human longevity.

Risks

Early Stage Technology: The project's reliance on a relatively untested method in higher organisms – using light energy for mitochondrial stimulation – is a significant risk.

Long Development Timeline: From initial research to clinical trials and technological advancements for treatment of inner organs, the timeline can span many years, if not decades.

Complexity in Treating Aging: Aging is a complex and multifactorial process. While the project aims to address several aging-related issues simultaneously, the interplay of these factors in aging is not fully understood.

Luminova pitch recording and transcript

Senior Review

Senior Review Digest - Quantitative Below is the average scores out of 5 per category from 4 reviewers, who all recommended that the project should be advanced for token-holder vote.

Average Scores Team Expertise: 3.75 Feasibility & Data: 4 Commercial Potential & Impact: 3.5 Novelty & Market Advantage: 4 IP Defensibility: 4 Relevance to Longevity: 4 Evaluation summary: 3.75 Deal Terms: 3.5 General Conviction Score 3.8 (for reference, the average score of past funded projects is 3.7)

Senior Review Digest - Qualitative Reviewer 1 Overall positive. Appreciates the novelty, potential market entry due to existing therapies, and the project's alignment with their interests in exploration and innovation. Questions the technology's maturity, specificity to certain pathophysiological mechanisms, effects on mitochondrial function beyond ATP production, and potential immune responses to foreign protein expression.

Reviewer 2 Overall positive. Highlights the strong team, appropriate choice of the eye for initial trials, step towards mammalian systems, and translatability to human diseases. Commends the novel mechanism and overall strategy. Expresses concern over the clarity and complete understanding of the mechanism.

Reviewer 3 Acknowledges the novelty of the technology and the strong scientific team. Concerns about impact on disease indication; Doubts about the technology's ability to significantly impact human disease due to unclear benefits of increased mitochondrial activation; Notes the complexity of the system and its modest increase in lifespan, questioning the translatability to viable therapy.

Reviewer 4 Overall positive. Acknowledges the project's success in demonstrating a proof of concept in C. elegans and recognizes the significant market potential for treating age-related vision loss. They find the project's goals reasonable and achievable within the set budget and timeline. They highlight the novelty of using optogenetics. The main concern about the technology's applicability beyond the eye and its dependence on light for effectiveness.

Bibliography

Full proposal on Discourse.