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

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

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

Longevity Dealflow WG team

  • Senior Reviewers: Review process has not been initiated yet
  • Shepherd: Maria Marinova, Jason Mercurio
  • 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

Aging is characterized by an increased prevalence of the cellular and molecular hallmarks of aging, which include mitochondrial dysfunction, accumulation of metabolic toxic byproducts, and systemic decline of the body vasculature. The hallmarks of aging are interconnected and a central challenge is to have a suitable and efficient treatment addressing several hallmarks at once.

Older individuals suffer from age-associated vision loss and an increased prevalence of metabolic diseases, such as diabetes, which together impair eye function (Fig 1.). Specifically, reduced oxygen transport, mitochondrial dysfunction, and accumulation of lipofuscin are involved in vision loss with aging and related maladies.

The aim for Luminova is to improve the aging phenotype with a novel approach using vision loss as an early-stage proxy. The Luminova team has developed a novel technology that can directly overcome these age-mediated dysfunctions in the eye.

Fig 1. Prevalence of late AMD according to age and gender in Caucasians from industrialised countries

Solution

Luminova addresses the interconnected hallmarks of aging, including mitochondrial dysfunction, the accumulation of metabolic waste, and systemic decline. Recognizing the challenge of finding a treatment that addresses multiple hallmarks simultaneously, they aim to offer a comprehensive solution. The company strategically uses eye aging as an early-stage proxy for their innovative approach.

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 (Fig 2.).

Fig 2. Mitochondria-ON (mtON) increased ∆ψm in vivo. The mitochondrial inner membrane (IM) contains the electron transport chain (ETC), which pumps protons to generate mitochondrial membrane potential (∆ψm). mtON is an engineered light-activated proton pump and, in response to light and ATR supplementation, pumps protons across the IM to generate ∆ψm

Berry, Brandon J et al. “Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.” Nature aging vol. 3,2 (2023): 157-161. doi:10.1038/s43587-022-00340-7

The use of optogenetics to control mitochondrial membrane potential, previously demonstrated as a novel method to partially restore mitochondrial functions (Qiu et al., 2022), is a new approach for harnessing the energy of light to directly power mitochondria and sets Luminova apart in the field of aging research. This innovative approach opens a new subfield in aging research.

The company outlines a comprehensive pre-clinical trial plan in mice, focusing on the eye. This involves assessing the biodistribution of mtON, determining its functionality in isolated mitochondria, and evaluating the therapeutic benefits in the context of age-associated vision loss and diabetic retinopathy.

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 (Fig 3.). Addressing age-related vision loss presents a substantial market opportunity, and if successful, the technology could potentially be extended to address issues in other organs.

Fig 3. Bourne, Rupert R A et al. “Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis.” The Lancet. Global health vol. 5,9 (2017): e888-e897. doi:10.1016/S2214-109X(17)30293-0

The technology developed by Luminova Biotech, known as mitochondria-ON (mtON), addresses the critical issue of mitochondrial dysfunction, which is recognized as a central factor in the aging process. The technology’s ability to optogenetically increase mitochondrial membrane potential during adulthood using a light-activated proton pump represents a groundbreaking approach with significant potential to impact aging projections (Fig 4.).

Fig 4. Model showing effects of mtON activation in vivo. The dotted arrow represents the molecular mechanisms to be investigated that link mitochondrial membrane potential (Δψm) to aged physiology.

Here are key reasons why this technology presents a great opportunity to change aging projections:

  • The use of optogenetics to modulate mitochondrial membrane potential is a sophisticated and precise approach. Optogenetics involves using light to control cells that have been genetically modified to respond to light stimuli, providing a high level of control over cellular processes.
  • Focusing on mitochondrial membrane potential as a target is strategic, given its central role in aging. The technology directly addresses the decline in mitochondrial membrane potential associated with aging.
  • While the initial experiments were conducted in C. elegans, the ultimate goal is to translate the technology to humans. The fact that mitochondrial function is a conserved aspect across species increases the potential relevance of the findings to human aging.
  • The technology not only extends lifespan but also improves age-associated phenotypes. This implies a potential to enhance overall healthspan (Fig 5.), addressing not only longevity but also the quality of life in the later stages.

Fig 5. mtON extended lifespan and healthspan. Light treatment began at day 1 of adulthood for all experiments. a, Survival curves of mtON-expressing animals (extrachromosomal array). Only mtON activation (+ATR +light) significantly extended lifespan, log-rank (Mantel–Cox) test, *P = 0.019. Detailed statistical information for all lifespans is presented in Supplementary Table 1. b, Survival curves of mtON-expressing animals (CRISPR insertion). mtON activation significantly extended lifespan compared to the light control by log-rank (Mantel– Cox) test, *P = 0.0001, gray and light-green curves.

Berry, Brandon J et al. “Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.” Nature aging vol. 3,2 (2023): 157-161. doi:10.1038/s43587-022-00340-7

Luminova’s long-term vision involves upgrading mtON for functionality in inner organs. The hypothesis is that whole-body mtON gene therapy can increase human longevity. This ambitious goal positions the company to explore broader applications beyond the initial focus on eye aging.

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. The team will also assess the accumulation of metabolic waste byproducts, such as lipofuscin. 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. The team will test the benefits of mtON activation over time and measure whether less metabolic byproduct waste accumulates with time in the eye and if mtON treatment delays the onset of age-associated vision loss.

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. The team will administer AAV-mtON to mice before and after STZ injection and evaluate the preventive and post-injury therapeutic potential of mtON. The team will follow similar assessments as described in section A.

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. Funding, profits, and decision-making processes are shared, with specific conditions outlined for when Luminova regains full control of the project and how profits are distributed among token holders. Finer details will be ironed out in ongoing negotiation.

  1. Timeline

Relevance to Longevity

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

The ambitions of the project aims to demonstrate that the treatment, starting with the eye, could be an approach to slow down or reverse aging in the entire body since many age-related diseases are associated with mitochondrial dysfunction, the technology’s positive influence on mitochondrial health may have preventive or therapeutic implications for diseases such as cardiovascular disorders, neurodegenerative conditions, and metabolic diseases. This method uses solar energy to increase the body’s energy production, a novel and new approach that isn’t yet available on the market.

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

Shahaf focuses on novel approaches to extend healthy lifespan, including enabling metazoans to harness the energy of light and translate it to chemical energy in their mitochondria.

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

Andrew uses optogenetics to study the role of site-specific ROS production in mitochondrial physiology and hypoxic stress signalling. His work developed the mtON technology to control mitochondrial function using light.

Peter Hungerford

  • Luminova Biotech, CFO

Peter graduated from Syracuse University with a degree in Accounting and Economics and built a real estate portfolio of over 1,000 units. To date, his cumulative transaction volume is in excess of $5 billion.

Strengths

Innovative Approach: Luminova’s focuses on rejuvenating mitochondrial function through the groundbreaking use of optogenetics, presenting a novel approach to address multiple aging hallmarks simultaneously.

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. The technology directly addresses the decline in mitochondrial membrane potential associated with aging, presenting a holistic solution.

Application to Aging Phenotype: The project aims to improve the aging phenotype by targeting age-related vision loss as an early-stage proxy. This strategic focus allows for comprehensive pre-clinical trials, particularly in mice, with the potential to extend to broader applications beyond the initial eye aging scope.

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. This ambitious vision positions the project to explore broader applications beyond the initial focus on eye aging.

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. The effectiveness and safety of this approach in long-term human applications remain to be thoroughly validated.

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. However, the application to the eye would be aided by a precedent set for gene therapy approval for eye administration.

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. This complexity could pose challenges in accurately assessing the treatment’s efficacy and potential side effects.

Luminova pitch recording and transcript

Senior Review

In the process of collecting reviews.

Bibliography

Luminova Main Papers

On improving mitochondrial functions

Visible lights reduces longevity in C.elegans

Advances in Ophthalmic Optogenetics

Optogenetics against senescence

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The recording and transcript are behind a sign-in.

Targeting the eye seems a reasonable start, but I don’t see any eye people on the team. Is the goal to target the RPE, the macrophages, the neurons, muscles around the lens or what?

What strain of mouse will be used? IIRC, B6 and some other inbred strains have a genetic predisposition to blindness.

What cells account for the longevity phenotype in C. elegans? It’s not clear there will be any benefit to the eyes.

If there’s no change to respiration in the worms, despite an increased mitochondrial membrane potential, why is the presumption membrane potential instead of some compensatory mechanism to manage energy homeostasis in the worm? Maybe it’s lower energy demands on the mitochondria that lead to less damage. Did feeding the worms FCCP change the measured mitochondrial potential? It’s not clear how robust the phenotype is.

From a big picture standpoint, reducing energy input/increasing autophagy seems associated with longevity, but mtON should boost the amount of energy produced instead of reducing it. What about worms that get rapamycin plus the mtON/light/ATR? Is the longevity boost synergistic, additive, or no change?

Another possibility is that the mtON cells turn over more rapidly due to high membrane potential, which clears out senescent cells, and contributes to lifespan that way. This could be a major problem if it shortens the lifespan of any of these eye cells. If it targets senescent cells, not sure the eye will be the best model to start.

Why TMRE+Mitotracker Green instead of JC-1?

From an approach standpoint, not sure AAV is the best delivery vehicle. There seem to be no plans to test durability of expression, ability for repeat dosing or longevity of the transfected cells. On one hand, eyes should shut down immunity to the foreign antigen, on the other hand if you break tolerance, they’ll go blind.

It seems like there are a lot of unknowns that need to be solved first. Seems like R03 territory for me.

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Good morning and thanks for your comments.

We are supported by Dr. Dorota Skowronska-Krawczyk who is an eye expert from UCI. She is part of our team and guides us with the experimental design. We are now starting biodistribution of mtON injection in the mouse eye with the CRO Experimentica. We will also then assess the toxicity and durability expression of the mtON.

The strain of mice that we will be using is Balb/c mice.

We did not try rapamycin - an interesting idea. However, we did find additive lifespan increase with constitutively active AMPK in worms. Adding FCCP has abolished the lifespan increase by mtON.

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The recording is behind a sign-in because there were some confidential data disclosed in the pitch.
Whoever’s interested can request access which is granted if NDA is in place.
cc @gweisha

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Double checked. B6 go deaf, not blind. That was my mistake.

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hi @Shahaf this is very cool science and great work @m_marinova, @Ageless_Partners, and Squad for putting together an innovative commercialization proposal. The reasons I’m still somewhat on the fence have to do with translatability and freedom to operate.

Can you get some sense from the published literature that augmenting mitochondria in the way the mtON would be expected to do would work well for AMD? Perhaps this might help answer @bowtiedshrike’s questions about the mechanism of the longevity effects.

Also AAV seems fine for PoC mouse studies but I’d like to see the pros and cons to this vs. other arguably safer approaches such as lipid nanoparticles.

Lastly, I would think the orginators of optogenetics, because they are at well-resourced institutions, might be a barrier to your claims of having “exclusive rights”. Can you comment on how you will have and maintain freedom to operate? I don’t know the field but I imagine the original patent holders did something like what happened with CRISPR where basically anything fell under their patents.

This is decades away. There are real animal models for this. Worms? There are AAV animal models for this that are clinically validated. There are already drugs out there. The space is crowded with next gen tech.

We cannot keep giving “grants” for good science and basic research. We need commercially viable assets. That’s what brings value to VitaDao and patients.

If we don’t start investing in commercially viable assets and IP we are going to become a research foundation that doesn’t profit or get anything approved.