One-liner: Utilizing simulated microgravity to accelerate cellular aging for rapid drug screening against aging and age-related diseases.
Longevity Dealflow WG team
Senior Reviewers: [To be completed after Senior Review]
Shepherd: @tdinhVitaDAO
Other squad members: @gweisha , @m_marinova , @Paolo
Sourced by: @tdinhVitaDAO , @gweisha , @m_marinova
Project PI: David Furman, PhD, Scott Ginebaugh, PhD
Simple Summary
Microgravity environments, such as those experienced by astronauts aboard the International Space Station, induce a phenotype of accelerated aging in living cells and tissues (1,2). This effect can be replicated in cells in a lab on Earth by using technological platforms that simulate microgravity conditions (3-6). Cosmica has created a drug development platform in which simulated microgravity is used to rapidly age cells until they develop age-related disease profiles to screen therapeutic compounds for aging and age-related diseases in a high-throughput manner.
Preliminary data from neural and cardiac organoids has demonstrated that accelerated aging induces Parkinson’s Disease and Dilated Cardiomyopathy phenotypes, respectively. In contrast to Cosmica’s proprietary genetically normal models of Parkinson’s, many in vitro Parkinson’s disease models are created by genetic engineering cells to express rare familial mutations that cause early onset Parkinson’s. However, these mutations are not representative of the overwhelming majority of Parkinson’s patients, who develop the disease through aging rather than genetic mechanisms (7). Furthermore, Cosmica’s disease models utilize human cells and human-derived organoids – rather than animal models. Thus, our disease models are substantially more accurate, less expensive, and faster than in vivo animal models. The implementation of 3D organoid models subject to simulated microgravity for drug discovery and development is in line with the FDA modernization act 2.0, which aims for a future without the use of laboratory animals and recognizes the use of these in vitro systems as preclinical evidence for disease biomarkers and drug development.
Cosmica’s system is highly flexible, and appears to be capable of inducing accelerated aging in cells from any organ. As a result, this will become an extremely powerful tool, accelerating preclinical development of novel compounds for numerous age-related diseases and aging itself.
Problem
90% of drugs fail clinical trials. This statistic is even worse for age-related diseases: drugs for cardiovascular disease, Alzheimer’s, and sarcopenia have 94%, 98%, and 100% failure rates, respectively. $140 Billion dollars per year are spent on R&D for drugs that end up failing clinical trials.
The main reason drugs fail clinical trials is lack of efficacy, rather than toxicity or side effects. Increasing evidence indicates that this lack of translatability is largely due to differences in exposures and genetics between laboratory animal models (usually inbred mice) and humans. For instance, human lifespan is 40x longer than mice, which makes these models particularly inaccurate compared to the biology of human aging and age-related diseases. More generally, from basic genetic constituents that determine mice biology (size, lifespan, circadian rhythms, etc.) to environmental exposures, mice seem to be poor models for human disease (8). Furthermore, animal models are low throughput, time-consuming, and expensive. Alternatively, recent developments are incorporating in vitro models for age related disease by engineering in rare familial mutations that cause early-onset versions of these diseases. However, these rare mutations likely do not reflect the cellular biology that causes these diseases through aging in a majority of the disease patients.
Solution
Comica’s technology induces an accelerated aging phenotype in 3D organoids, allowing for the rapid increase in the biological age of these stem-cell-derived models. These aged models will increase the efficiency of longevity research and enable rapid, accurate, high-throughput screening of compounds for their abilities to improve longevity, slow the aging process, and treat age-related diseases.
To create new models for age-related diseases, the impact of simulated microgravity on a healthy organoid model is examined. The microgravity induced signatures are then mapped to disease profiles from human ‘omics data. Hence, this approach is, in principle, disease agnostic and can be implemented to target the diseases that are best modelled by simulated microgravity in 3D organoids from any organ system.
Once the age-related disease model has been developed, it can be used to perform high-throughput screening. Drugs, nutraceuticals, and gene knockdown/knockout screens can all be performed in a high-throughput fashion. Cosmica’s standard pipeline involves knockdown/knockout screens to identify the optimal gene target, and then screening small molecules that hit the identified gene target.
Cosmica’s technology has demonstrated efficacy of the simulated microgravity approach in three different systems:
- Immune Cells: The manuscript describing this proof of concept has been accepted in Nature Communications.
Here, after exposing peripheral blood mononuclear cells (PBMCs) to simulated microgravity for 25 hours, accelerated aging was observed as the increase in biological aging according to an epigenetic clock, a decrease in the immune response to Toll-like Receptor agonists 7/8 and increase in inflammaging gene signatures, an increase in cellular senescence gene signatures, and an alteration in the mechanical properties of the cell.
By mapping the simulated-microgravity induced gene signature to signatures of disease from human data, enrichment analysis demonstrates that changes in gene expression due to simulated microgravity are highly indicative of diseases like cardiovascular disease, atherosclerosis, and vascular inflammation. These results suggest that simulated microgravity induces an age-related inflammatory response that leads to the build up of atherosclerotic plaques, which are directly linked to causes heart attack.
A proof-of-concept in silico screening was then implemented to select compounds that would be expected to induce a transcriptomic response opposite that of the transcriptomic response induced by simulated microgravity.
One of the top compounds was quercetin, a natural compound with known anti-senescent and anti-inflammatory effects that has been suggested as a potential treatment for heart disease (note: Cosmica is not planning on developing quercetin as a therapeutic – this is only for Cosmica’s proof-of-concept phase). Pre-treatment with quercetin was able to cause a partial reversal in the microgravity-induced gene signature, and was able to cause a reduction in age-related inflammation.
In summary, the proof of concept experiments were successful in demonstrating that Cosmica’s technology is able to induce accelerated aging, link the aging signature to age-related disease, identify potential treatments for those age-related diseases, and test the efficacy of compounds in vitro.
- Cardiac organoids: For Cosmica’s demonstration of efficacy on 3D organoid models, simulated microgravity was applied to cardiac organoids. By utilizing a transcriptomic clock based on human heart aging from Genotype-Tissue Expression (GTEx) database and then applying the cardiac aging clock onto transcriptomic data from 3D iPSC-derived cardiac organoids at normal gravity (1G) or at simulated microgravity, Cosmica’s model shows cardiac organoids experience accelerated aging by approximately 5 years in 25 hours. The mapped signatures of microgravity against disease profiles demonstrates that microgravity conditions in these cardiac organoids map best to dilated cardiomyopathy.
Cardiac organoids naturally display a heartbeat, and functional analysis of these cardiac organoids show a profound decrease in heart rate after exposure to simulated microgravity conditions.
- Neural organoids: Lastly, the accelerated aging was applied to neural 3D organoids derived from iPSCs. The simulated microgravity induced an approximately 15 year increase in transcriptomic age and mapped most strongly to synucleinopathy, which includes neurodegenerative diseases such as Parkinson’s disease and dementia with Lewy bodies. We also identified microgravity-induced transcriptomic changes in cellular mechanisms, such as protein folding and metabolism, that are also highly perturbed in neural aging and Parkinson’s disease.
Opportunity
Cosmica’s approach of using space biology to study aging is unique; the technology Cosmica develops will not only help create therapeutics and products to treat aging and age-related diseases, but will also create new models which will improve the speed, efficiency, and accuracy of longevity research.
This technology was spun out of David Furman’s lab at the Buck Institute for the Research on Aging. David is Cosmica’s Chief Science Officer and is one of the leading experts on age-related inflammation and space biology. Christpher Mason – the head of the NASA Twins Study and PI of the Axiom 2 and SpaceX Inspiration4 missions – is also a co-founder and member of the Scientific Advisory Board. Cosmica CEO brings a high level of expertise on computational biology, transcriptomics, and organoid models from his work at the Broad Institute and Dana-Farber, and the Head of R&D is a leading expert in sequencing technologies and cell culture techniques.
Relevance to longevity
Cosmica’s technology accelerates the mechanisms of aging, allowing for the high-throughput study of aging, age-related diseases, and compounds that treat aging and diseases of aging. The goal is to develop a platform that will lead to the creation of treatments that target age-related diseases and the mechanisms of aging.
The main leadership is composed of experts in aging and biology. The CSO, David Furman, is an Associate Professor at the Buck Institute for Research on Aging and the Director of the 1000 Immunomes project at Stanford. The CEO, Scott Ginebaugh, was formerly a computational biology postdoctoral researcher at Dana-Farber Cancer Institute, the Broad Institute, and Harvard.
The Scientific Advisory Board includes Daniel Winer, an associate professor at the Buck Institute, and Christopher Mason, a professor at Weill Cornell. In addition, J. Gene Wang and Joan Mannick bring decades of expertise in drug development from the pharm/biotech industry.
IP Roadmap
Cosmica has filed the main patent, which covers the use of simulated microgravity to help develop compounds for the treatment of aging or age-related diseases. This patent is owned by the Buck Institute and licensed to Cosmica. The license is exclusive, worldwide, and sublicensable. By utilizing the technology described by this patent, Cosmica will develop therapeutics targeting the aging-induced changes that cause neurodegenerative diseases.
Experimental plan
Stage 1: Further develop our in vitro neural models and improve our high-throughput screening capabilities. We expect to complete this stage by Q3 2024.
Stage 2: Perform high-throughput gene knockdown screening to identify optimal target to reverse neural aging and treat Parkinson’s. We expect to complete this stage by Q1 2025.
Stage 3: Develop and screen compounds to reverse the aging mechanism identified in Stage 2. We expect to complete this stage by Q4 2025.
Stage 4: Prepare for clinical trials with toxicity screening and further validation of lead compound. We plan to begin Phase 1 trials by the end of 2026.
Budget
Stage 1: 6 months (platform generation)
- Organoid generation experiments: $180,000
- Disease accuracy validation: $120,000
- Legal: $50,000
- Salaries: $180,000
- Overhead (15%): $80,000
Subtotal: $610,000
Stage 2: 6 months (target validation)
- Round 1 : $ 120,000
- Round 2: $ 80,000
- Salaries: $180,000
- Overhead (15%): $60,000
Subtotal: $440,000
Stage 3: 12 months (compound screening)
- $1.1M for medicinal chemistry against lead target identified in stage 2, in vitro screening of compound efficacy, and selection of lead compound.
Stage 4: lead IND preparation
- $900K for toxicology screening, PKPD, and preparation of IND application.
Total: $3,050,000
Financing and VitaDAO Funding Terms
Cosmica Bio is looking to initially raise $200,000 from VitaDAO members. They are currently raising a total of $2M at a valuation of $8M, of which they have already closed $300,000. VitaDAO is part of Cosmica’s larger fundraising strategy, which also includes traditional VC funding, government grants, and revenue-generating partnerships.
This project will be funded via a Sponsored Development Agreement. This will grant VitaDAO rights to participate in the commercial success of a company asset. All rights and operational responsibility remains at the company.
Cosmica will retain ownership of the IP, while using IP-NFT and IPT technology for project management and governance. A summary of the business terms are as follows:
- Royalty payments in favour of VitaDAO with a dynamic royalty rate linked to the company valuation
- Buy-out exit scenario for VitaDAO in case of equity financing and change of control event at company
- Matching rights for VitaDAO to obtain project IP in an IP transfer event initiated by company
- Project IP transfer rights for VitaDAO if company does not proactively pursue the funded programme
Team
Leadership
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Scott Ginebaugh, PhD – CEO & Co-founder – Former postdoc at Dana-Farber, Harvard, and the Broad Institute, Former computational biologist at Garuda Therapeutics
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David Furman, PhD – CSO & Founder – Associate Professor at the Buck Institute, Director of Stanford 1000 Immunomes Project, Founder of Edifice Health
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Michael S. Granitsiotis – Head of R&D – Former Associate Director at Stilla Technologies
Key Collaborators
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Allison Duettmann – Business Advisor – President & CEO of the Foresight Institute, author of Gaming the Future
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Dan Winer, MD – Scientific Advisor & Academic Co-founder – Associate Professor at the Buck Institute, Associate Professor at the University of Toronto
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Chris Mason, PhD – Scientific Advisor & Academic Co-founder – Academic Co-founder, Professor at Weill Cornell Medicine, PI of the NASA Twins Study
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Prakash Nanduri – Business Advisor – VP of Product Management & Strategy at Docusign, Co-founder & former CEO of Paxata
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Joan Mannick, MD – Scientific Advisor – Co-founder of ResTORbio, co-founder of Tornado Therapeutics, Medical Director at Genzyme
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J. Gene Wang, MD, PhD – Scientific Advisor – Founder of Immetas Therapeutics, former Clinical Development & Translational Medicine at GSK, former Director of Immunology Early Development at BMS
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Bryan Cox, PhD – Scientific Advisor – Senior Director of Computational Chemistry at Terremoto Biosciences, Former Principal Scientist at Atomwise
Slide deck
Highlights
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Multiple applications: Mapping microgravity-induced signatures to a number of disease profiles offers a method for modeling and targeting age-related diseases across organs and even cosmetic applications.
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Team Expertise: The founding team and scientific advisory board cover expertise across drug development, space and computational biology and the biology of aging.
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IP Defensibility: The team has secured a key patent owned by the Buck Institute, exclusively licensed to Cosmica. This covers the use of simulated microgravity to develop compounds for treating aging or age-related diseases, providing global protection and sublicensing options.
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Relevance to Longevity: Aligns with VitaDAO’s funding mandate, to support moonshot longevity projects.
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Availability of Data: Proof of concept of data is available.
Risks
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Validity of Model Systems: While the proposal suggests that the simulated microgravity models are more accurate and representative of age-related diseases compared to traditional animal models, there may still be limitations in how well these models reflect human physiology and disease progression. Validation against clinical data and human samples is necessary to ensure the relevance and reliability of the findings.
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Unforeseen Side Effects: Accelerated aging induced by simulated microgravity may result in unforeseen cellular responses or side effects that could affect the interpretation of drug screening results.
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Regulatory Hurdles: The unique approach proposed here, involving the use of simulated microgravity and organoids, may face additional regulatory challenges.
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Technical Risks: This is still quite an early stage project. There is no guarantee that the proposed approach will identify new and robust targets for neural aeging and Parkinson’s.
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Disease Indication Risk: Parkinson’s Disease is a complex, poorly understood condition.
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Drug Development Risks: Even with a novel target, developing a new drug that can work on the target is complex and high risk of failures.
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Timeline: The proposed timeline for development and clinical trials seems ambitious. significant financial implications.
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Competitors: Other startups are proposing to conduct ageing experiments in actual space.
Bibliography
- Biolo, G., Heer, M., Narici, M., & Strollo, F. (2003). Microgravity as a model of ageing. Current Opinion in Clinical Nutrition and Metabolic Care, 6(1), 31–40. Microgravity as a model of ageing : Current Opinion in Clinical Nutrition & Metabolic Care
- Malhan, D., Schoenrock, B., Yalçin, M., Blottner, D., & Relόgio, A. (2023). Circadian regulation in aging: Implications for spaceflight and life on Earth. Aging Cell, 22(9). https://doi.org/10.1111/acel.13935
- Nishimura, Y. (2023). Technology using simulated microgravity. Regenerative Therapy, 24, 318–323. Redirecting
- Shi, L., Tian, H., Wang, P. et al. Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways. Cell Mol Immunol 18, 1489–1502 (2021). Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways | Cellular & Molecular Immunology
- Clary, J. L., France, C. S., Lind, K., Shi, R., Alexander, J. S., Richards, J. T., Scott, R. S., Wang, J., Lu, X.-H., & Harrison, L. (2022). Development of an inexpensive 3D clinostat and comparison with other microgravity simulators using mycobacterium marinum. Frontiers in Space Technologies, 3. https://doi.org/10.3389/frspt.2022.1032610
- Investigation into Stimulated Microgravity Techniques used to Study Biofilm Growth - NASA Technical Reports Server (NTRS)
- Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012 Jan;2(1):a008888. doi: 10.1101/cshperspect.a008888. PMID: 22315721; PMCID: PMC3253033.
- Pollen, A.A., Kilik, U., Lowe, C.B. et al. Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution. Nat Rev Genet 24, 687–711 (2023). Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution | Nature Reviews Genetics
Other relevant manuscripts
- Francine E. Garrett-Bakelman et al. ,The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science364, eaau8650(2019). DOI:10.1126/science.aau8650
- ElGindi, M., Sapudom, J., Garcia Sabate, A. et al. Effects of an aged tissue niche on the immune potency of dendritic cells using simulated microgravity. npj Aging 9, 14 (2023). Effects of an aged tissue niche on the immune potency of dendritic cells using simulated microgravity | npj Aging
- da Silveira WA, Fazelinia H, Rosenthal SB, et al. Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact. Cell. 2020;183(5):1185-1201.e20. doi:10.1016/j.cell.2020.11.002
- Afshinnekoo E, Scott RT, MacKay MJ, et al. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration [published correction appears in Cell. 2021 Nov 24;184(24):6002]. Cell. 2020;183(5):1162-1184. doi:10.1016/j.cell.2020.10.050
- Ludtka, C., Silberman, J., Moore, E. et al. Macrophages in microgravity: the impact of space on immune cells. npj Microgravity 7, 13 (2021). Macrophages in microgravity: the impact of space on immune cells | npj Microgravity
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