One-liner: Discovery and development of a novel antiglycation and anti-crosslinking agent aimed at decreasing ECM stiffness.
This proposal is based on the supporting documents provided by Dr. Roman Litvinov and Alexey Strygin, as well as questions and answers to their team, and senior reviews.
Longevity dealflow WG team
Initial evaluation: Joppe Nieuwenhuis, Diane Seimetz, Anonymous reviewer (prof.)
Final evaluation: Diane Seimetz, Tim Peterson, Nina Patrick, Jean Hebert
Sourced by/Shepherd: Rakhan Aimbetov
Squad members: Estefano Pinilla, Paolo Binetti, Max Unfried, Laurence Ion
Project PI: Dr. Roman Litvinov
4/4 senior reviewers have expressed a vote in agreement to staged funding for this proposal. Here is the digest:
To quantify the level of conviction, the reviewers provided a score on a scale of 1-5 (with 5 being the highest).
The average score was 2.9/5.0.
Brief qualitative review summaries:
Under consideration of the various discussions and potential concerns, the proposed approach to de-risk the project by a staged approach starting with a $30k fund to conduct a short PoC study in an experimental glycation animal model is endorsed. For the decision making on the follow-on funding, the totality of data, i.e. from the animal study as well as the in vitro data, should be considered.
I favor funding the first two milestones up to $155K but I recommend any additional funds should require external capital.
The staged financing makes sense, which I endorse. It’s more likely with the current in vivo testing focus that whatever they end up testing has a positive health effect, regardless of glycation status or mechanism of action, and so even if it means a pivot, may have commercial value.
I am supportive of the first financing tranche of €30K for the team to demonstrate traction and de-risk the project to attract outside investment.
Intra- and intercellular components constantly get non-enzymatically modified by simple sugars and reactive glycolytic metabolites in a process known as glycation. This is especially true for long-turnover proteins such as collagen, elastin, fibronectin, etc. found in the extracellular matrix (ECM). Advanced glycation end products (AGEs) that form as a result of glycation often exist as irreversible crosslinks between ECM components and/or as adducts on ECM molecules. The accumulation of AGEs leads to the loss of matrix elasticity and its stiffness, as well as the activation of receptors for damage-associated molecular patterns (DAMPs), mechanistically linking glycation to a wide range of deregulatory processes characteristic of old age and associated diseases. Some reports propose ECM glycation and downstream effects (stiffness, etc.) as a new hallmark of aging that drives cellular senescence, stem cell exhaustion, chronic systemic inflammation, and other pathogenic processes.
Notably, elevations in AGEs with consequent collagen-based cardiomyocyte and extracellular matrix stiffness [link], as well as glycation-related aseptic inflammation [link], are among the pathogenetic mechanisms of diabetic cardiomyopathy (DbCM). The project is aimed at screening a library of natural plant extracts for the discovery of novel compounds that would inhibit the ECM glycation process within the context of DbCM as a surrogate indication.
As discussed at longevity dealflow working group meetings and in the designated thread in the WG Discord channel, in order to critically evaluate the project’s feasibility and attractiveness in terms of fundability, the applicant team is asked to show proof-of-concept (PoC) efficacy of extracts in an in vivo model. Consequently, the team is asking $30k (see Experimental plan and Financing and milestones/First financing stage: $30k sections below) to conduct a short PoC study in an experimental glycation animal model.
If the PoC experiments show sufficient efficacy of extracts, the proposal will be re-voted on with the full experimental and IP set-up in scope.
VitaDAO’s available funds
For context, VitaDAO funded 15+ projects with $3.5m+, and has ~$4.5m in liquid funds remaining (before further fundraising), which will be used for:
- Funding new projects (such as this)
- Operations, including sourcing, incubation, evaluation, & community growth
- Follow-on funding, including for projects VitaDAO will spin out
Natural aldehydes and ketones such as glucose, fructose, and galactose, as well as reactive dicarbonyls glyoxal and methylglyoxal, react with biological amines – e.g. N-terminal and side-chain amino groups in amino acids, phosphatidylethanolamine, phosphatidylserine – to form various adducts and crosslinks. These non-enzymatic modifications, given enough time, become irreversible and constitute so-called advanced glycation end-products (AGEs).
AGEs accumulate with age and contribute to age-related pathologies via several routes:
Adducts such as carboxyethyllysine (CEL), carboxymethyllysine (CML), fructosyl-lysine, etc, bind to receptors of the RAGE (receptors for AGEs) family and stimulate inflammatory reactions.
Modified proteins, on the other hand, sustain disruption of their tertiary structure and elicit unfolded protein response which, if unchecked, can contribute to the loss of proteostasis observed during aging and diseases like Alzheimer’s, Parkinson’s, etc.
Crosslinks such as glucosepane, pentosidine, MOLD, MODIC, etc. covalently tether proteins together interrupting their normal function.
For intracellular proteins, the aforementioned modifications are bearable since most proteins have a relatively fast turnover rate and their pool is constantly replenished (although there is evidence for histone glycation and subsequent negative consequences). However, in the case of long-lived proteins, glycation can have a prolonged detrimental effect. This is especially true for proteins of the ECM because these proteins have half-lives which are considerably longer.
Crosslinking of ECM proteins – collagen, fibronectin, elastin – leads to the rigidity of the matrix. The accumulation of crosslinks has a profound effect on blood vessel elasticity and places an increasing strain on the cardiovascular system. Moreover, several reports show that stiffness of the ECM is the sole factor that can promote cellular senescence and dampen stem cell differentiation.
There are several means to ameliorate the effects of ECM glycation. Firstly, it is to break existing crosslinks either enzymatically – the approach currently developed by Revel Pharmaceuticals. However, given the multitude of various crosslinks and adducts, this approach requires an array of interventions each aimed at a specific glycation end product.
An alternative approach is to attenuate glycation, and this modality has been tried with the compound aminoguanidine. This synthetic compound, however, did not pass clinical trials due to safety concerns. Since naturally-derived therapeutic molecules generally have better safety profiles, it is reasonable to turn to natural sources for the discovery of new drugs with antiglycative characteristics.
It should also be noted that in a recent paper – “New hallmarks of aging” – glycation-associated ECM stiffness is considered both a hallmark and one of the pathogenetic mechanisms of aging. This adds to the importance of having interventions targeting glycation in the portfolio of longevity assets.
There are 12.9M patients with DbCM in the 7 largest Western Nation countries. Current treatment approaches focus on clinical manifestations of DbCM and hemodynamic disturbances rather than on pathogenetic mechanisms. One of the approaches with good efficacy evidence [link 1, link 2] is SGLT-2 inhibitors. They have decent efficacy in the prevention of CVD-related deaths and hospitalizations, a decent safety profile, and medium-to-high costs. If at least one of these parameters can be improved upon, there is a good chance to capture a considerable share of this market.
Hypoglycemic agents with cardioprotective properties, such as SGLT-2 inhibitors, etc., have limited potential as longevity therapies due to the high likelihood of causing hypoglycemia in non-diabetic patients. They argue that if our candidates exhibit a substantially improved safety profile, even bigger market (prevention of diabetic cardiomyopathy in high-risk patients diagnosed with type 2 diabetes (T2D), metabolic syndrome, or prediabetes) will become available.
Plant-derived polyphenols (extracts) were shown to be effective against various cardiomyopathies including DbCM, combining different pro-longevity mechanisms of action (MoA), such as mTOR regulation and modulation of its downstream effectors (not only antiglycation activity).
The Boston Matrix team is planning to screen over 2500 natural plant extracts, isolate and develop a novel therapeutic candidate. The MoA would include antiglycation activity, prevention of ECM cross-linking, and amelioration of ECM stiffness. Previously, they have used this approach to sсreen for a number of existing natural compounds/extracts and novel chemically synthesized molecules.
The team has access to a collection of 2500+ natural extracts (and means to identify, isolate and modify active ingredients to make patentable products with drug-like properties) and to a library of 500+ natural compounds (mostly novel) already isolated from these extracts. Additionally, they have an in silico platform and tools for the discovery and optimization of ECM stiffness-ameliorating molecules. The platform and the tools are trained on 199 molecules (isolated, modified, or chemically synthesized) with a proven antiglycation effect [Russian patents RU2021623030, RU2021622654].
Most natural plant extracts contain polyphenols, flavonoids, anthocyanidins, and other active compounds. Preliminary trials have shown that quercetin, luteolin, and tannin possess remarkable antiglycation activity in in vitro tests done in their lab (IC50 for quercetin is ~3 μg/ml; for tannin – less than 1 μg/ml). Green tea and grape seed extracts have high concentrations of polyphenolic compounds and also show high antiglycation activity (3-6 μg/ml). The initial screens of the first 50 of 2500 extracts had shown leads with antiglycative properties far exceeding those of quercetin and the reference compound aminoguanidine [report0]. Subsequent studies identified several leads that exceed the stated IC50 value (Chamarhodos sabulosa, Swida sanguinea, etc. [report1]). Additional research has shown that lead extracts were able to stimulate mitochondrial metabolic processes (as judged from the MTT assay) exerting cytovitalic (opposite to cytotoxic) action [link]. At the same time, reference antiglycator quercetin elicits cytotoxicity in the same concentration range.
This and the whole history of pharmacology suggests that plants are a great source of efficacious and safe compounds. The applicant’s philosophy for preclinical development is based on testing the activity of compounds in ever more complex (and costly) test systems weeding out unpromising candidates along the way. They will use the simplest in vitro tests modeling pathology (in this case – the glycation process) for initial screening. After that, the leading candidates will be tested in cellulo. They do not plan in vivo studies validating the ability of lead isolated compounds to suppress cardiomyopathy in diabetes or prolong life in laboratory animals at this stage as they will not be able to fit the trials in a 12-month timeframe and in the budget. However, to determine the ability of lead extracts to act as a source of potential antiglycating agents, it is planned to utilize a quick in vivo model that verifies the ability of the extract components to penetrate the biological barrier of the gastrointestinal tract and remain stable in amounts sufficient to exhibit antiglycation activity. The model assumes subchronic methylglyoxal intoxication (intraperitoneally, 17.25 mg/kg, equivalent to that produced in diabetics) combined with oral administration of an extract.
Potential non-aging indications for regulatory approval are T2D and its long-term complications (nephropathy, angiopathy, etc., as well as cardiomyopathy, selected as a surrogate indication), cardiovascular diseases, Alzheimer’s disease, and other proteopathic neurodegenerations (in complex treatment). Targeted hallmark – loss of extracellular proteostasis (ECM cross-linking is considered a stand-alone hallmark of aging; link). Other possible applications of the platform with faster time-to-market are the cosmetic dermatology industry, cosmeceuticals, and nutraceuticals.
The described preliminary work was obtained by scientific groups which included Roman Litvinov, and was published in peer-reviewed journals [link1, link2, link3].
Evidence supporting the concept that increased ECM stiffness is associated with glycation [link 1, link 2], can negatively affect cell and tissue properties [link], and has a negative impact on longevity [link] is plentiful. The most relevant manifesto reflecting this notion has been published in the recent “New hallmarks of aging”:
“Altered mechanical properties apply both to cells and to the extracellular milieu … Finally, the extracellular matrix also changes with ageing, which greatly alters cell behavior. Increased rigidity and loss of elasticity, for example arising through glycation cross-links between collagen molecules, can lead to multiple age-related disease states such as hypertension with concomitant kidney and neurological defects – such cross-linking may contribute to the accelerated aging seen in patients with diabetes”.
The above quote also confirms the appropriateness of choosing CVDs (and DbCM in particular) as a target indication since matrix crosslinking contributes to increased vascular stiffness, abnormal vascular response, arterial hypertension, and (eventually) cardiac pathology. Outside the context of aging, this mechanism is particularly relevant to diabetes.
Target product profile
|Target population||- Patients with T2D and diabetic cardiomyopathy
- Patients with T2D and at risk of CVDs (label extension)
- Patients at risk of prediabetes, metabolic syndrome, atherosclerosis and exposure to high-AGE food (longevity label extension)
|Therapeutic modality||Small molecule (isolated from natural extract or modified)|
- 40%+ lower 3-year risk of CVD-related death vs placebo
- 35%+ lower 3-year risk of heart failure hospitalisation
Secondary and label extension outcomes (% changes TBD):
- Lower progression stage B to overt heart failure (stage C)
- Percentage of blood ejection before and after 12 weeks of treatment
- Change of LVEF between before and after 12 weeks of treatment
- Peak VO2 during cardio-pulmonary exercise test (CPET); [15 months after randomization]
- Change in myocardial perfusion reserve index calculated from cardiac MRI
- HbA1c, general fluorescent AGEs level (which includes pentosidine, vesperlysines A, B, C, crossline, fluorolink, FFI etc.)
- Pulse-wave velocity
- Ankle-brachial index
|Safety||Generally very well tolerated (important for longevity).
Incidence of adverse events:
- Hypoglycemia (<1%)
- UTIs (<5%)
- Nausea (<1%)
- Upper respiratory tract infection (<2%)
|Mechanism of action||Anti-glycation agent|
|Biological activity||- Lower hypertension incidence due to less of vascular fibrosis and AGEs in the vasculature (i.e. less stiffness of vessels)
- Lower tissue levels of AGEs
Thus, systemic effect on cardiomyopathy progression.
Stage 1 (already started and ongoing):
- Preparation and initial screening of 2500+ natural plant extracts to assess their antiglycation activity (~4-5 months):
The purpose of this stage is to assess the antiglycation activity of 2500+ natural extracts rapidly and cost-effectively in an assay modeling accelerated glycation. The team will monitor glycation end products (for all extracts) and intermediate products of glycation (for lead extracts). Progressively, as they weed out more extracts, they will make the assay more complex by introducing additional parameters (e.g. temperature – increased to accelerate glycation/equal to body temperature; ion composition – presence/absence of transition metals). This is aimed at improving the specificity of the results (variations in the buffer used, temperature, glycating agent, glycated protein, etc., as well as the detection method, are required in order to more fully describe dominant mechanisms of antiglycation activity and confirm the activity of leads). Cytotoxicity studies of the most promising candidates are also planned for this stage.
- Short-listing and further analysis of lead natural extracts. Confirmation of the antiglycation activity of the leading extract in an in vivo model. Initial talks with patent attorneys. [additional 2-4 months after the end of stage 1]:
- additional assessment of antiglycation activity using ELISA
- exploration of antiglycation activity mechanisms (antiradical, carbonyl scavenging, metal chelation)
- short in vivo model to confirm the activity in living organisms
ELISA with anti-AGEs antibodies will be used to confirm the results of in vitro. The dominant mechanism of the leads’ antiglycation activity is planned to be studied using a triplet of tests (antiradical activity, carbonyl scavenging, inactivation of transition metals). The activity of the best leaders will be tested in a brief animal model to evaluate the ability to suppress the advanced glycation induced by methylglyoxal subchronic intoxication. This test will be used to confirm the activity of extracts in an animal model (PoC).
- Testing the activity of isolated active compounds (3-4 months after stage 2):
- preparative chromatography
- additional exploration of antiglycation activity and detailed mechanisms thereof
- exploration of complementary activities (carbonyl scavenging, transition metals scavenging, antiradical activity, etc.)
- cytotoxicity evaluation
- analysis of markers associated with cellular response to glycation products (MMPs, ILs)
Optimizing the lead candidate structure via the in-house developed AI-powered tool and medicinal chemistry techniques. Optimized structures will not be tested for activity at this stage. However, it still will be possible to protect the most promising compound and derivatives.
Preparation of materials for patenting (single or combined identified compound(s) and(or) virtually assessed compound and (if relevant) derivatives thereof) and subsequent scientific publication.
As the most promising extracts are selected, the team will be identifying active ingredients in these extracts by LC-MS. When the contents of extracts are identified, the team plans to apply preparative chromatography techniques and test the activity of isolated compounds repeating stages 1-2.
Promising leads will be tested in cellular models to determine the ability to influence the important markers of aging and DbCM pathogenesis. The team plans to test a relatively narrow range of markers that change due to glycation. The long-listed markers are cellular AGE levels, inflammatory cytokine levels (IL1b, IL6, IL8, TGFb, and other), metalloproteinase levels (MMP2, MMP9, TIMP1, and other). The final choice of markers will depend on the results of the first experiments. Part of these trials is planned to be outsourced. Considering the groupability of markers, if one of the two groups of markers is successfully influenced, the analysis will be expanded towards this group of markers. At present, it is impossible to predict with sufficient accuracy which particular group of markers will be affected by a particular compound.
If necessary, in silico optimization of most promising leads (based on quantum chemical QSAR-analysis neural network optimized for improving antiglycation effect – trained on datasets already available and those that will be generated during the experiment) will be applied.
Description of the assays and methods
In their work, the applicants use screening of a wide range of candidates, highlighting the main and additional methods of research.
The whole-extract antiglycation activity screening assay was devised by the team and published in peer-reviewed journals [link 1, link 2, link 3].
The initial screening technique is based on the reaction of glycation of albumin (the main model protein) with glucose (a common glycation agent) with applied heat (to stimulate the reaction) and detection of fluorescent glycation products at 5 or 10 different pairs of excitation/emission wavelengths; 2 pairs of excitation/emission wavelengths corresponding to fluorescent amino acids and some additional parameters (if necessary). The approach was preliminarily characterized here.
A large number of wavelength pairs correspond to different AGEs (namely pentosidine, vesperlysine A and B together, vesperlysine C, fluorolink, FFI, crossline, lysyl-pyrrolidine), and some oxidation products are used for minimization of interference from the test extractives. The activity results estimated at some wavelengths are not taken into account if the extracts show the ability to quench fluorescence at this pair of wavelengths. Only data at non-interfering pairs of wavelengths are used. Additional assessment of the amino fluorescence (namely, tryptophan and tyrosine) is aimed at testing the ability of the compound to prevent the loss of the native protein conformation during the glycation reaction. This provides a reliable result of the initial screening of the antiglycation activity.
The estimated bandwidth of the initial antiglycation quantification model is at about 2500 extracts/5 months. To increase the assay throughput, the glycation reaction will be sped up by heating the reaction mixture to 60C in PBS pH 7.4. The team had determined all key parameters of their model, reflected in the Methods section of their first reports [report0, report1], and in one of the demo study protocols [link].
The condition for passing the screening will be an IC50 of less than 3 μg/ml (at present, the applicants have already established several extracts with IC50 values as low as 0.4 μg/ml, which means that the first milestone is achieved: Chamarhodos sabulosa IC50 0.4-1.4 ug/ml, Swida sanguinea IC50 ~0.46 ug/ml, Sedum hybridum IC50 ~0.37 ug/ml, Oenotera biennia IC50 ~0.7 ug/ml [report1] (IC50 values will be updated because some values in these initial studies were extrapolated). The 3 ug/ml concentration in the first milestone had been included based on the activity of green tea extract with high (95%) content of polyphenolic fraction which contains a strong antiglycation agent epigallocatechin gallate. As a reference, they use functionally, and structurally close compounds (tannin, quercetin), as well as the well-known antiglycation/deglycation molecules some of which were evaluated in clinical trials as anti-AGE agents (aminoguanidine, alagebrium, etc.), and molecules used clinically for other indications with known antiglycation activity (pyridoxamine, hydralazine, etc.).
Further analysis allows the possibility of testing the activity using proteins other than albumin (gelatinized collagen) and glycation inducers other than glucose (methylglyoxal, glyoxal, fructose, etc.) – as an example, a protocol for studying albumin glycation with various glycation agents at two different temperatures is attached [link] – as well as probing the activity of the lead extracts in the test system using ELISA and glycation temperatures equal to the human body temperature. At body temperature, the ELISA assay will require extended incubation (for 28 days) of reaction mixes since the ability of antibodies to detect AGEs diminishes if glycated albumin had been heated to 60C. The results of tannin’s antiglycation activity assessed in the 28-day model (fluorescence in 5 concentrations, ELISA in 2 concentrations) is available via the following link [link].
Parallel to finding the most promising extracts, they also plan to perform preliminary analyses of the extracts’ dominant MoA zooming in on three modalities: the ability to scavenge carbonyl compounds, the ability to bind transition metals, and their antioxidant action. All mentioned models are fine-tuned, methodologies described [link 1, link 2, link 3].
Moreover, they also plan to determine the polyphenolic content of our extracts, since all well-known plant bioactive compounds with antiglycative properties belong to the class of polyphenols [link].
The study is expected to be combined with an assessment of toxicological properties in cell cultures. A sample protocol describing cytotoxicity assay in HepG2 cells using MTT is accessible via [link]. According to preliminary data, some lead extracts – possessing antiglycation activity in the ng/ml concentration range – possibly are able to stimulate mitochondrial metabolic processes (exerting cytovitalic, i.e. not cytotoxic, action). NB: the medium containing the extract was removed before adding the MTT reagent, therefore the observed effect is most likely not due to extract interference. At the same time, the reference compound quercetin elicits cytotoxicity in the same concentration range.
The lead activity will be evaluated in an in vivo model designed to test for the capacity to suppress the advanced glycation, induced by subchronic methylglyoxal intoxication. They have devised a technique that allows for complex analysis of compounds’ antiglycative properties. The technique entails subchronic intoxication with methylglyoxal (17.25 mg/kg intraperitoneally, which is equivalent to amount generated in diabetic patients) combined with oral administration of tested extract/compound [link 1, link 2]. Since molecules absorbed from the visceral peritoneum, mesentery, and omentum are drained into the portal vein, whereas molecules absorbed from the parietal peritoneal capillaries and lymphatic vessels are drained directly into systemic circulation [link], the experiments will be concluded by extracting liver autoptates and serum collection followed by a comparative quantification of the AGE content. The model has been calibrated by the scientific team using ALT-711 as a reference compound and can be applied to testing the whole extracts’ bioavailability, activity retention in the biological milieu, and suppress glycation in vivo (PoC).
For compound isolation, they will utilize preparative chromatography coupled with validation by mass spectrometry. First of all, they plan to check the activity of all (or at least the most promising) isolated compounds in a battery of screening assays as described for whole extracts. It’s entirely possible that at this stage they’ll show that varying activity components are associated with distinct compounds. Should this be the case, they’re considering the possibility of compound combinations.
In the assays employing cell cultures, in addition to the direct detection of AGEs, an immediate marker of glycation, they plan to carry out the assessment of the influence of substances under study on the production of MMP2 and MMP9, as well as IL-1b and IL-6, by fibroblasts in response to the glycated cellular environment. These molecules serve as important predictors of myocardial remodeling and associated negative outcomes [link 1, link 2]. The said markers are either immediate ECM remodelers (metalloproteinases) or markers of aseptic inflammation indirectly linked to remodeling; if any of the groups shows to be regulated by glycation, they’ll expand their analyses in the direction of the affected group. Presently, it’s impossible to predict which markers will be affected by any given substance.
They have defined a surrogate indication – diabetic cardiomyopathy. The proposed markers are prominent in both the aging process and the surrogate indication. The markers can be divided into two groups: 1. linked to aseptic inflammation and inflammaging (pathogenically associated with aging [link] as well as with diabetic cardiomyopathy [link], and elicited by AGEs), such as IL-1, IL-6, IL-8, TGF-b, etc.; 2. linked to matrix remodeling (associated with aging [link] and diabetic cardiomyopathy [link], and brought about by AGEs in the ECM), such as MMP2, MMP9, TIMP1, etc.
At the final stages of the project, they will take advantage of our in silico platform – in order to ensure the patentability of the result (not for screening purposes). A compound modeled using the quantum chemical QSAR model will have a greater potential to become an IP than an isolated natural substance. All the while, in silico tests are optional because increasing patentability prospects may not be required if an isolated active substance itself – as decided by a patent attorney – will be the object of IP.
Limitations: whole extracts or isolated components of extracts can be difficult to patent. This limitation is addressed by introducing the QSAR neural network-based lead optimization, as well as collaborations with synthetic chemistry experts to model the potential modification (virtual leads) and assess the technical and economic viability of synthesis/production.
Since Open Longevity (OL) – a parent company for Boston Matrix – is non-profit, the applicant team is not positioned to develop a commercial product beyond discovery and PoC trials. The team plans to start negotiating patenting options upon receiving their first results as indicated in the work plan (stage 2) and file for a patent concluding the experimental part of the project (stage 3). The team will require assistance from VitaDAO in filing for a patent and sees the DAO as the IP holder. Further IP strategy might include protection of an optimized lead, use of lead(s) vs particular indication(s), formulation and production process.
This application is the first stage of the ROADMAP to solving the problems of ECM stiffness and glycation in aging. The team expects more opportunities for IP generation to become available in the future.
Roman Litvinov, M.D., Ph.D. in pharmacology and clinical pharmacology, head of group. Academic positions: senior researcher, assistant professor. Scientific interests: molecular biology of glycation reaction, pharmacological control of glycation reaction, advanced glycation end product (AGE) inhibitors, crosslink breakers, receptor for AGEs (RAGE), AGEs-associated pathologies, metabolic disorders. Several molecules Roman has worked on proceeded to clinical trials.
Alexey Shavarda, Ph.D., provides a unique collection of 2500+ plants from territories of Eurasia: Kazakhstan, Kyrgyzstan, and Russia.
Alexey Strygin will be responsible for turning the project into a commercializable IP, business networking, and organizational support.
Umida Ibragimova, researcher, PhD student.
Alina Rzaeva, researcher, PhD student.
Nikita Valuysky, researcher, student.
Marina Gasheva, researcher, student.
Angeline Shushakova, researcher, student.
Open Longevity is a non-profit that possesses a vast network of longevity scientists, engineers and enthusiasts, and encompasses a number of initiatives aimed at accelerating aging research. OL team members will be responsible for general project management and coordination, PR, and IR: Mike Batin (founder), Anastasia Egorova (CEO), Timofei Glinin, Ph.D. (CSO)
|Initial screening in in vitro assays of glycation, insights into mechanisms, initial in vivo study||$40-55k|
|Secondary screening of most promising candidates (initial mechanism of action of the leader extracts)||$40-50k|
|Isolation, identification of active ingredients of short-listed candidates||$15-25k|
|Initial mechanism of action and cytotoxicity studies (in partner lab or CRO)||$100k|
|Patenting and other various costs||$10-15k|
|Video filming and production||$15k|
Financing and milestones
First financing stage: $30k
- PoC in an in vivo model of extracts’ antiglycation activity.
Second financing stage: $115k
The funding is contingent on the lead extracts’ performance in vivo on par with the reference compound quercetin.
- A short list of candidate extracts (1 or more) with antiglycation activity (IC50 3 μg/ml or less; if translated to humans it would roughly approximate to the effective dose of 150-300 mg of unmetabolized compound taken orally assuming uniform distribution), initial assessment of MoA and verification of antiglycation activity in the PoC in vivo model.
Third financing stage: $155k
1 or more isolated compounds with high antiglycation activity. Detailed MoA and pharmacological properties;
Filed patent application to protect the above-mentioned compound(s);
A video documentary (no less than 20 minutes long) describing all the development stages is filmed and edited. VitaDAO funding is mentioned in the beginning and in the end of the documentary.
Important note: due to the separation of the project into 3 milestone groups, the overall timeline might increase as some processes that could have been done in parallel will be performed sequentially.
The group possesses unique experience in a relatively new field – glycation reaction and crosslinks as a target for longevity interventions.
Their preliminary PoC data show a promising antiglycation effect of several natural plant-derived compounds.
In vivo experiments to confirm the antiglycation activity of extracts will be conducted.
IC50 of these compounds is two orders of magnitude lower than the reference antiglycation compound aminoguanidine and up to 10 times more active than quercetin which suggests a better safety profile.
The team has access to the Open Longevity talent pool.
The initial screening will be done in vitro. Lead molecules might not be as effective in vivo (the risk will be addressed by the addition of PoC tests in an in vivo model).
The inhibition of glycation could have no effect on already glycated macromolecules, therefore only delaying damage accumulation rather than repairing (despite the possibility of limited efficacy, the team has a general roadmap that has the potential to be effective against already formed advanced glycation end products, and the current project is the first stage of that strategy).
It might not be possible to isolate active compounds or isolated compounds will not be amenable to synthesis (the risk will be mitigated due to the expectedly large number of leading extracts).
There’s a risk of not procuring sufficient contingent funding for the Third financing stage.
The war between Russia and Ukraine may interfere with the applicant team’s ability to make progress (harder access to consumables/need to relocate the lab).
At present, the team asks for $30k to show PoC efficacy of their extracts in an in vivo murine model. Please vote below if you think the team should be funded with the requested amount.
- Agree with revisions (please comment)