VDP-29: Exosomes for treating systemic inflammation

Longevity Dealflow team

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

Simple Summary

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.

Problem

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.

Opportunity

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:

  1. They preserve the anti-inflammatory properties in vivo
  2. Their delivery can be achieved non-invasively via intranasal administration
  3. 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.

IP Roadmap

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.

Endpoints

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:

  1. Characterizing anti-inflammatory exosomes for regulatory QA/QC requirements.
  2. Modifying exosomes from different sources (not necessarily MSC-derived) with specific compound to acquire anti-inflammatory/pro-neurogenic properties.
  3. Possible application of the identified compounds or pathway-related compounds by themselves without exosomes as conventional drug therapy.

The endpoints for each stage are:

  1. Stage 1: a list of 20-50 preliminary candidate compounds
  2. Stage 2: completion of in vitro and in vivo tests for each preliminary candidate compound

Potential Future Directions

  1. Expand to other disease models in mice for Alzheimer’s disease, rheumatoid arthritis, multiple sclerosis, etc.
  2. Track and detect engraftment and localization of naïve and antiinflammatory exosomes in vivo.
  3. Determine the optimal route of administration: intranasal, intravenous, and oral administration (depending on a disease model and desired effect).

Team

Dr. Gadi Turgeman, PhD, DMD, Head of The Stem Cell Research Lab.

https://www.ariel.ac.il/wp/gadit/

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

https://fohs.bgu.ac.il/research/profileBrief.aspx?id=VuidMuiVi

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).

Budget

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
Total: 				            	$275,000

Strengths

  • 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

Risks

  • 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
  • Agree with revisions (please comment)
  • Disagree

0 voters

3 Likes

Awesome work everyone putting together this proposal. All longevity WG VDPs should follow this format. On first glance it reads well, but there are several serious issues:

  1. IP plan: Does the team have a differentiated plan of action to generate IP? They disclose that exosomes will be produced from “PACAP-treated MSCs polarized to anti-inflammatory MSCs”. Thus, that can’t be the IP because it is publicly disclosed. And yet, it is noted that the field is highly competitive so presumably many people are pushing in the same direction to polarize cells to be anti-inflammatory. It’s important that a clearly articulated, proprietary plan to generate IP already exists. Do they have a novel exosome isolation method that produces more reliable or higher concentrated exosomes? Will they use PACAP + some other mystery compounds? Will some specific stem cell line produce the most anti-inflammatory exosomes? Currently, the proposal lacks insight into how the team will outcompete the competition.
  2. budget: The budget reads like a science project. The two stages/milestones should be focused on: 1) producing the IP; 2) validating the IP. We don’t need -omics and certainly not $72,000 worth in generating the IP. The screening process that will generate the IP should be an inexpensive biomarker. Once the IP has been identified, the validation (stage 2) should also be the cheapest, fastest in vivo study one can do to prove the exosomes can work. Omics aren’t useful at this stage. Just think about it: Any pathway worth caring about for the in vivo study can be measured by a biomarker.
  3. efficacy: A big problem with exosomes is they aren’t reliably effective. The proposal says itself: “preliminary data shows modest improvements…”.
  4. commercialization: Related to lack of efficacy, exosomes are hugely complex compared to small molecules or gene therapies. There is a reason many experienced biopharma people stay out of these types of therapies. They are very difficult and expensive to manufacture consistently.
  5. disease indication: What’s the disease indication? Without a target how can one know what bioassays should be done to validate the exosomes?
9 Likes

Wouldn’t be more straightforward to figure out what in the exosomes produces the anti-inflammatory effects or is this known? A specific mix of cytokines/other molecules produces the effect? Is the exosome delivery method superior to small molecule/biological delivery?

3 Likes

Caveat: this is my first time reviewing a proposal for VitaDAO, but I have served as a grant reviewer in the past for non-profits for projects ranging 10 - 750K.

In general, I think this is a worthwhile area of research and the project seems worth undertaking, but this proposal is incredibly lacking considering the funds proposed. I agree also with Tim’s previous comments and will provide some brief additionals here for the authors to consider:

This feels like half of a proposal, as there’s no execution strategy outlined. The introduction also provides no literature trail which is frustrating / unsure why that format is acceptable. I see that the scientific team helping out on this is familiar with the research but naive readers are not.

  1. experimental design - what studies exactly are being undertaken here? What is the previous research and how does the proposed research build on this / differentiate. Is it even necessary to have a post-doc and a Ph.D. student working on this? If so what are their roles? Far greater scientific details need to be provided. What are the key studies being taken, outcomes expected, how does this translate to the patent strategy. What will occur over the 10 month timeline?

  2. what IS the patent strategy, especially if this area is difficult to own? I would think patent via process (A + B)? That needs to be defined, mapped out, and defended.

  3. I’d like to see some brief comments around scalability

7 Likes

It’s a very good point @kdl that identifying the specific factors that cause the anti-inflammatory effect could make this project more feasible.

1 Like

Thanks everyone for your valuable input. Check out the updated proposal! We’ll have a call Tuesday at 15 UTC with the applicant and TTO representative to negotiate IP sharing terms and finalize any outstanding points

1 Like

A more in depth description is available internally (in the dealflow funnel - Sign in - Airtable).

If you don’t have access feel free to DM me.

1 Like

If negotiations go well, before phase 3, I’ll post the conviction level and summary reviews.

1 Like

One point I want to highlight that makes public discussion of patents and IP due diligence tricky is that anything publicly disclosed is no longer patentable (or a potentially patentable trade secret) anywhere in the world (although you do have a 12-month grace period in the US).

Therefore, discussions with the evaluation team must be under NDA and that team needs to be careful not to disclose specific methods or chemical formulas of compounds to anyone else unless they are under NDA as well.

Something to be aware of and not sure if this is already taken into account by the Dealflow team. This does mean we are in a bit of a catch-22 situation for community-powered desci projects like where the broader VitaDAO community may necessarily have to rely on the patentability due diligence undertaken by the relevant WG and have less information available which they can use to make an informed vote.

3 Likes

Agreed @Savva. What’s important to convey publicly is that we have conviction that the team does have an IP plan. Clearly in some cases the team doesn’t have a well-thought out plan. This is not uncommon because academics getting grants vs. securing IP are two fundamentally different activities and academics are only trained in the former often without much knowledge on the latter. The tokenholders should know that we don’t want the team to disclose the plan, but simply that the team has one and it seems credible.

1 Like

Correction on my earlier comment. We don’t need the team to tell us the full plan. In many cases, telling people the full details of one’s plan will jeopardize it. Meaning, it’s unfair for us to require them to tell us the “how” (unless they want to share). What we do need to figure out is whether we think they have a good plan. A team can provide information that makes us aware that they know what they are doing. This will give us convinction on whether we should bet on them.

For example, in the case of this exosome project, if the team would proactively address questions like I proposed above, then our conviction would increase.

Due to potential changes in the budget and overhead negotiation, the requested range in phase 3 will be $250k - $350k

I expect this to go for a phase 3 vote in 7 days (will include senior reviewers final quantitative score and qualitative remarks )

2 Likes

I’m very skeptical of exosome work in the first place because there are a lot of artefacts in that field.

How rigorous were the preliminary data? (eg EM for exosomes, exosome purity, which mouse strain/disease model/“inflammaging” markers, how robust was the phenotype, if they used IF for neurogenesis, was it quantitated and well-controlled, how many exosomes did it take)? Did exosome prep adhere to ISEV guidelines/is there an exosome person advising on this?

Stage 1 looks like a fishing expedition, but unclear how synergies between compounds will be tested. It is unlikely to be one single active compound. Not clear how any list will be prioritized-- is there a negative control of MSC-derived vesicles that do NOT reduce “inflammaging”?

If the active(s) they find already has/have well-known anti-inflammatory properties, how does this end up as IP?

How is a postdoc going to be supported for only $56k? What about fringe? Does VitaDAO cover tuition for the PhD student?

2 Likes

I would guess this would be just part of the work they might be doing. Postdocs don’t get paid much; it could be a whole year of salary at some institutions. For the tuition of the student, that is usually covered along with a small stipend from the PI’s grants or institutional funds.

Regarding the rest above, I think you have some great questions to consider. The proposal should be a little more in depth to help answer these concerns.

2 Likes

I don’t have time to read the above paper at the moment, but I thought I would link it to your comment so I can come back to it and perhaps someone else will find this interesting. I agree, there should always be citations and references.

Current NIH funding for a postdoc with 0 years experience is $54,835. Fringe usually includes health insurance, and possibly other benefits, so add another 15-20% to the base salary for those. Is the pay really that much lower in Israel? Or is this 0.5-0.75 FTE (full-time effort)?

For a PhD student, NIH recommends $26,353. The extra $8k could be tuition, but that would be incredibly cheap for a whole year. Not sure how insurance is handled at the institution, but $34k seems high for salary, low for benefits.

2 Likes