Longevity Dealflow team
Scientific evaluation: Sebastian Brunemeier, Tim Peterson, Rhys Anderson, Koen De Lombaert
Business evaluation: Sebastian Brunemeier, Tim Peterson
Shepherd/Sourced by: Tyler Stahl
Squad members: Paolo Binetti, Rhys Anderson, Rakhan Aimbetov, Ryan Spangler
Project PI: Vera Gorbunova
Naked mole rats (NMR) are long-lived rodents with a lifespan of up to 40 years, compared to normal rats which live about 3 years. Unlike other rodents, NMR are found to be cancer resistant. Previous research by the Gorbunova lab has demonstrated cancer resistance in NMR is modulated by the abundance of high molecular weight hyaluronic acid (HMW-HA) in tissues (1). Additional research has demonstrated that transgenic mice expressing naked mole rat hyaluronan synthase gene (NHAS2) have less tumours, improved health, and live 10% longer than mice without the transgene (2). To increase HA in human patients and translate these findings into the clinic, this project will screen and develop small molecule inhibitors of hyaluronidases, the enzymes that break down hyaluronic acid. These compounds can be used for cancer treatment and are expected to increase human healthspan and lifespan.
VDP-45 on Decentralised Tech Transfer outlined a new model of funding which, in collaboration with academic partners, conducts experiments at CRO or “fee-for-service” academic facilities. In brief, DTT allows for greater efficiency with treasury resources, speed of project initiation, and the ability to reward research collaborators for their effort.
VitaDAO is launching a newco with the Gorbunova lab, called Matrix Pharma. A term sheet has been signed, with the deal terms below that entails the incorporation of Matrix Pharma.
The overall population is aging, and aging is the major risk factor for nearly all human diseases, e.g., cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, and Alzheimer disease, to name a few. Cancer, specifically, accounted for an approximately 10 million deaths worldwide and had an estimated 19.3 million new cases in 2020 (3).
While cancer progression is predominantly associated with genetic driver mutations, a number of other critical factors have been identified that facilitate cancer initiation and progression, offering new therapeutic opportunities in cancer treatment. The tumour microenvironment is one such component, consisting of tumour cells, tumour stromal cells, endothelial cells, immune cells, and non-cellular components of extracellular matrix (ECM). Through complex signalling networks, tumour cells have the ability to use non-malignant cells to their own advantage, consequently leading to tumour formation and maintenance (4).
HA, a long polysaccharide found in the ECM, plays a multifactorial role in tumour suppression and progression (depending on the polymer size) through interactions with HA receptors such as CD44. HA polymers are degraded by three major hyaluronidases, HYAL 1-3. HYAL2 is specifically located at the cell surface, and together with reactive oxygen/nitrogen species (ROS/NOS), are responsible for breaking down HWA-HA (1-6 MDa) to low molecular weight HA (LMW-HA)(10-250 kDa). Cancer initiation results in changes in HA organisation and processing including increased HA synthesis and expression of hyaluronidases, resulting in the fragmentation of HA. LMW-HA is known to promote neo-angiogenesis, tumor cell migration, invasion, and proliferation. Contrary, HMW-HA promotes tissue homeostasis and prevents tissue metastasis, through CD44 interactions and signalling (5,6).
Using exceptionally long-lived and cancer-resistant animals provides a strategy to identify molecular mechanisms that support longevity and healthspan, potentially uncovering novel targets and/or pathways for translation to humans. NMR, based on their size, would not be expected to live past six years, yet in some cases, live beyond 30 years. NMR also rarely get cancer, are resistant to some types of pain, and can survive up to 18 minutes without oxygen. At advanced ages, their mortality rate remains lower than any other mammal that has been documented. As such, the NMR’s biology has garnered great interest from ageing researchers.
Based on published work by the applicant, where it was found that NMR cancer resistance is conferred by abundant HMW-HA in tissue (1), the authors propose to design inhibitors against hyaluronidases, the enzymes that normally degrade HA. Furthermore, very-high-molecular-weight HA (vHMW-HA) has superior cytoprotective properties compared to the shorter HMW-HA, protecting both human and mouse cells from stress-induced cell-cycle arrest and cell death (7).
Most recently, the Gorbunova lab has found that transgenic mice that express the NMR hyaluronan synthase gene have less cancer, show improved health, and live 10% longer than mice without the transgene, supporting that higher levels of HA promote healthy living and longevity (2). While humans cannot produce vHMW-HA, it is possible to increase HMW-HA and decrease LMW-HA by inhibiting the enzyme that breaks hyaluronans down, namely hyaluronidase 2 (HYAL2). The aims of the proposed studies now intend to develop and validate HYAL2 inhibitors in order to translate these research findings into clinical applications.
The Gorbunova lab has designed a complex and validating functional screening assay to find inhibitors of hyaluronidase 2 (HYAL2). A previous ~3k compound screen has led to discovery of one natural product that increases the levels of HA in mouse and human tissues. IP will include formulations and/or modifications of this natural product. Within the framework of the present proposal the team plans to perform larger compound high throughput screen (HTS) with the proprietary HYAL2 inhibition assay and medicinal chemistry optimization of hits to produce patentable new chemical entities.
A financing of USD 300k provided by VitaDAO, with 200k allocated to HTS and exploratory medicinal chemistry with a 3rd party CRO or academic ‘fee for service’ facility, and 100k allocated to the Gorbunova lab for hit compound experiments.
5k/month will be allocated towards consulting agreement
Program 1: HTS and med chem for new HYAL2 inhibitors
Phase 1: High Throughput Screening (HTS) – $100k
Phase 2: Medicinal Chemistry on hits – $100k
Program 2: Validation of existing in vivo active HYAL2 inhibitor (EC50 ~ 20 µM)
Administration of hit compound to mouse models of cancer to test for curative and
preventative effects - $100k
Funds will be used to assist in cover the costs related to:
Culturing human cancer cell lines for xenografts
Mouse evaluation for tumour burden
Milestones to be agreed in separate full length R&D plan.
Vera Gorbunova, PhD
Vera Gorbunova is an endowed Professor of Biology and Medicine at the University of Rochester and a co-director of the Rochester Aging Research Center. Her research is focused on understanding the mechanisms of longevity and on the studies of exceptionally long-lived mammals. Dr. Gorbunova pioneered a comparative biology approach to study aging. She elucidated the mechanisms that control evolution of tumor suppressor mechanisms. She uncovered the function of the longevity gene Sirtuin 6 in regulating genome stability across species. She demonstrated the role of transposable elements in driving age-related inflammation. Her work received awards from the Ellison Medical Foundation, the Glenn Foundation, AFAR, and NIH. Her work was recognized by the Cozzarelli Prize from PNAS, prize for research on aging from ADPS/Alianz, France, Prince Hitachi Prize in Comparative Oncology, Japan and Davey Prize from Wilmot Cancer Center.
- A novel idea from a world-leader in the field with extensive experience in longevity and healthspan mechanisms
- Strong published and supporting evidence for the target.
- May work against many types of cancer – high impact
- May address other Extracellular Matrix (ECM) and skin-related conditions, as well as: wound healing, arthritis and joint conditions
- Validated tool compound identified – showing that this target is druggable
- Strong IP potential with possible novel chemical matter (to be identified).
- Hyaluronidase inhibition may not be effective to improve health - most clinical hyaluronic acid data is limited to dermatology (skin aging), so unclear if it would work systemically to increase life/health span and reduce cancer in humans.
- Very novel and therefore still high-risk.
- Mixed literature evidence on the role of hyaluronan in metastasis.
- Expressing more NHAS2 enzyme (increased synthesis) is not entirely equivalent to reducing catabolism (HYAL1/2i). The authors previously published (Takasugi et al., 2020) that several cytoprotective effects of hyaluronic acid are driven specifically by vHMM-HA (>6MDa), which may be dependent on two naked mole rat-unique amino acid variations in the active site of hyaluronan synthase 2 (HAS2) and thus may not able to be produced in human cells even with hyaluronidase inhibition.
- Potential impact on the efficacy of chemotherapy and immunotherapy if taken in combination
This proposal has been reviewed by 8 senior reviewers, including: scientists, biotech business experts, a venture capitalist, and an MD.
The PI is a world leader in the field of comparative biology with a focus on longevity and healthspan mechanisms. They propose a unique approach with relatively little competition on the MoA and a straightforward road to NCE IP. There is strong published and supporting evidence for the target in mice. The mechanism for cancer prevention seems to be well established via CD44. There is already a screen hit with a potential asset in hand. This could be a first DeSci project, where the DAO is spinning out the company and that is a step forward for the community.
However, the hyaluronan role in cancer is somewhat controversial: on one hand, HMW-HA production is linked to cancer resistance, on the other hand, HMW-HA is involved in driving and maintaining malignant progression. The underlying hypothesis needs more PoC data to be further substantiated. It is unclear if the proposed intervention would work systemically to increase life/health span and reduce cancer in humans. No detailed plans are presented. The project is early and very high risk, but no insurmountable weaknesses.
The reviewers have scored the proposal on different aspects including general conviction, on a scale of 1-5 (with 5 being the highest). Here are the average scores:
- Novelty: 4.3
- Feasibility & Data: 3.5
- Relevance: 4.6
- Science Team: 4.6
- Market Advantage: 3.5
- IP Potential: 3.7
- Conviction score: 4.3
- Tian X, Azpurua J, Hine C, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;499(7458):346-349. doi:10.1038/nature12234
- Zhang Z, Tian X, Lu JY, Boit K, Ablaeva J, Tolibzoda Zakusilo F, Emmrich S, Firsanov D, Rydkina E, Biashad SA, Lu Q,Tyshkovsky A,Gladyshev VN, Horvath S, Seluanov A, Gorbunova V. Naked Mole-Rat Hyaluronan Synthase 2 Promotes Longevity and Enhances Healthspan in Mice. Preprint posted online August 8th, 2022. doi:10.2139/ssrn.4185135
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
- Baghban R, Roshangar L, Jahanban-Esfahlan R, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal. 2020;18(1):59. Published 2020 Apr 7. doi:10.1186/s12964-020-0530-4
- Gorbunova V, Takasugi M, Seluanov A. Hyaluronan goes to great length. Cell Stress. 2020 Jul 17;4(9):227-229. doi: 10.15698/cst2020.09.231.
- Liu M, Tolg C, Turley E. Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment. Front Immunol. 2019;10:947. Published 2019 May 10. doi:10.3389/fimmu.2019.00947
- Takasugi M, Firsanov D, Tombline G, et al. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020;11(1):2376. Published 2020 May 12. doi:10.1038/s41467-020-16050-w
- Agree with revisions (please comment)