Scientific evaluation: Sebastian Brunemeier, Diane Seimetz, Tim Peterson, Estéfano Pinilla, Aaron King, Todd White, Tovah Wolf, and anonymous reviewer (professor)
Business evaluation: Sebastian Brunemeier, Diane Seimetz, Tim Peterson
Shepherd: Laurence Ion
Other squad members: Jason Colasanti
Sourced by: Laurence Ion, via Mitya Toren
Project PI: Dr Gadi Turgeman
Chronic inflammation increases with age and contributes to several age-related diseases. Current anti-inflammatory treatments have unintended side-effects ranging from slight discomfort to life-threatening ailments. Dr. Gadi Turgeman has developed a novel anti-inflammatory therapeutic approach via stem cell-derived exosomes which have been shown to counteract aspects of brain aging, and improve cognitive function. The proposal consists of two main stages; in Stage 1 the team will perform multi-omic analysis on their anti-inflammatory exosomes to determine which molecules are responsible for counteracting brain aging, and in Stage 2 the team will perform in vitro and in vivo tests on the candidate molecules identified in Stage 1. The use of exosomes to treat age-related diseases may provide a more efficient and safer alternative to drugs since they do not contain any foreign chemicals with unknown mechanisms of action, which limits the possibility of off-target effects. Also, exosomes are a safer alternative to injecting stem cells since they may increase local inflammation and are at risk of transforming into cancer cells.
As we age, our cells become damaged, undergo stress, and produce pro-inflammatory cytokines. Increased inflammation combined with a declining immune system contributes to tissue dysfunction and exacerbates the development of age-related diseases. For these reasons, age-related chronic inflammation, also known as ‘inflammaging’, is a major focus of the aging and longevity field. Typically, anti-inflammatory drugs are prescribed to combat systemic inflammaging, however these drugs can have several side effects. Thus, an alternative method to safely reduce inflammaging is greatly needed.
Acute, low-grade inflammation is generally beneficial and necessary for proper immune system function and overall health. However, during aging, low-grade inflammation persists into a chronic state for reasons that are not yet known. This age-related chronic inflammation, a.k.a inflammaging, is detrimental to health and contributes to the overall aging process. Methods to safely limit inflammaging without inhibiting all instances of inflammation are currently lacking.
Gadi Turgeman and team have developed a novel approach to form anti-inflammatory exosomes from mesenchymal stem cells (MSCs) treated with the neuropeptide PACAP. Specifically, PACAP-treated MSCs polarized to anti-inflammatory MSCs. Their preliminary data demonstrated three key findings regarding exosomes derived from anti-inflammatory MSCs:
- They preserve the anti-inflammatory properties in vivo
- Their delivery can be achieved non-invasively via intranasal administration
- They can alleviate systemic inflammation, increase neurogenesis, and improve cognitive functions
This project will be carried out in two stages. The goal of Stage 1 is to identify RNAs, proteins, and/or metabolites that contribute to the beneficial cognitive outcomes seen in their in vivo mouse studies. The outcome of Stage 1 will be a list of 20-50 compounds that will be evaluated further in Stage 2. The goal of Stage 2 is to test the compounds previously identified in Stage 1 by loading them into exosomes derived from MSCs (without treatment of PACAP). These compounds will be individually assessed using in vitro and in vivo methods for their ability to reduce inflammation, improve cognitive functions. The outcome of Stage 2 will be the data generated from these experiments as well as a narrowed-down list of compounds shown to have beneficial effects. For their in vivo methods, old mice (18 months) will be used to accurately assess inflammation and decreases in cognition associated with aging.
In the past few years, interest in the field of exosome research for therapeutic potential has grown tremendously. This is in part due to the fact that exosomes deliver many of the benefits of stem cell therapy, but without the major risks. For instance, stem cell transplantation may result in the development of cancer cells. Conversely, exosomes can deliver the same intended cargo as stem cells, but lack the ability to replicate since they are not living organisms. Exosomes are small vesicles that are naturally produced by cells and can be specifically engineered to contain a wide array of nucleic acids, proteins, lipids, carbohydrates, or other types of molecules.
The applicants estimate that approximately one or one and half years will be needed to start patent registration. Intellectual property will most likely involve methods to generate stem cell-derived anti-inflammatory exosomes as well as their application for various inflammatory-related diseases. Fortunately, the technology proposed by Gadi and his team can be applied to virtually any inflammatory-related disease, thus potentially opening the door to a wide array of options for intellectual property. However, the patent landscape for exosome therapies has been highly competitive in recent years, so this process may be more difficult than expected. Currently, methods and patents already exist to reproducibly obtain exosomes in vitro for therapeutic use in vivo.
Overall, the goal of this proposal is to characterize and identify key factors and compounds responsible for the superior anti-inflammatory effect of exosomes derived from PACAP-treated MSC. This will allow for various routes to IP:
- Characterizing anti-inflammatory exosomes for regulatory QA/QC requirements.
- Modifying exosomes from different sources (not necessarily MSC-derived) with specific compound to acquire anti-inflammatory/pro-neurogenic properties.
- Possible application of the identified compounds or pathway-related compounds by themselves without exosomes as conventional drug therapy.
The endpoints for each stage are:
- Stage 1: a list of 20-50 preliminary candidate compounds
- Stage 2: completion of in vitro and in vivo tests for each preliminary candidate compound
- Expand to other disease models in mice for Alzheimer’s disease, rheumatoid arthritis, multiple sclerosis, etc.
- Track and detect engraftment and localization of naïve and antiinflammatory exosomes in vivo.
- Determine the optimal route of administration: intranasal, intravenous, and oral administration (depending on a disease model and desired effect).
Dr. Gadi Turgeman, PhD, DMD, Head of The Stem Cell Research Lab.
Specializes in MSCs molecular biology, genetic engineering and differentiation, with a focus on applications to neurodevelopmental diseases.
Prof. Vadim Fraifeld, MD, PhD, Head of the Lab for the Biology of Aging
Seasoned researcher in the biology of aging and longevity, with a special focus on cellular senescence, inflammaging, and cell reprogramming. Former Scientific Co-Manager of the European Large-scale integrating project RESOLVE (Resolve Chronic Inflammation and Achieve Healthy Aging by Understanding Non-regenerative Repair).
Stage 1: 10 months
Cell culturing and materials: $30,000 Omics: $72,000
Stage 2: 12-14 months
Cell culturing and materials: $21,000 Bioassays in vitro: $27,000 Bioassay in vivo: $35,000 Personnel Post-doc: $56,000 Ph.D. fellow: $34,000
- Using exosomes instead of stem cells avoids the risk of cancer transformation
- Novel method to treat inflammation and aging. Inflammaging is clearly relevant to the aging process and a major therapeutic target.
- It may work on brain aging – the major unmet need in the entire field (along with CVD).
- Non-invasive intranasal administration
- Exosome therapy is an attractive field at the moment and it’s being pursued via many angles.
- Since VitaDAO does not presently have any active research in this area, it makes a lot of sense to support this research and further diversify our portfolio
- The experimental plan is straightforward and likely to yield results
- The scientific team is strong, possessing the appropriate expertise and a consistent track record of productivity, including in the field of aging, to support the potential for success. Formalizing an interaction with them would be beneficial to all parties.
- There is strong initial preliminary data to support further research.
- Open to conducting lifespan studies and using various mouse models depending on the future funding.
- This technology can be applied to virtually any inflammatory-related disease, ranging from Covid-19 to inflammatory bowel disease and more.
- Beneficial effects of injecting PACAP-treated MSCs last up to 3 months
- The field of exosome research is very complex and still in its early stages
- Highly competitive landscape - further exploration on strength of IP is needed
- Unknown how long the beneficial effects of the exosome nasal spray treatment will last
- Preliminary data show modest improvements in cognition and only slight decreases in inflammation
- Testing in mouse bone marrow derived MSC and exosomes may not have the same effect in human bone marrow derived MSC
- They propose to eventually analyze MSCs as well
- A single compound in exosomes may result in the expected outcome
- In this case they will perform combinatorial engineering with several compounds, which will take additional time, effort, and resources
- Agree with revisions (please comment)