Notes on the SENS Research Foundation Pitch Day, January 2020

The J.P. Morgan Healthcare conference runs every year in San Francisco, a big draw for the biotech industry, and many organizations take the opportunity to host events at the same time. Among these, the SENS Research Foundation has for the past few years hosted a pitch day in which biotech companies in the longevity industry, largely startups, present to that portion of the Bay Area investor community interested in funding the treatment of aging as a medical condition. I was there to present on progress at Repair Biotechnologies, and took some notes on the other companies as they talked about their work.

Kimera Labs

Kimera Labs is a fairly established company working on exosome therapeutics and diagnostics, deriving the exosomes used in therapy from cultured stem cells. They have been around for 10 years or so, and started selling exosomes in 2014. They are primarily concerned with regenerative medicine applications, accelerating regeneration from severe injury via exosome delivery to produce faster healing without scar formation. Kimera Labs exosomes have been used to treat about 30,000 patients. The founder views the effects of stem cell exosomes as being a stimulation of growth signaling that is characteristic of embryonic development.

Viscient Biosciences

Viscient Biosciences works on 3D bioprinting of human tissues for drug discovery and validation, allowing for development programs that are, in their earlier stages, more cost-effective than those that must rely on animal studies. For example, they create liver organoids arrayed by the hundred on plates that are used in the processes of drug screening and testing. The company is founded by the former Organovo CEO. While they are not currently working on rejuvenation, the principals want to take their work into that realm of drug discovery.

OncoSenX

OncoSenX is the spin-out from Oisin Biotechnologies that applies the Entos Pharmaceuticals fusogenic lipid nanoparticle platform to the task of selectively destroying cancer cells. These lipid nanoparticles are non-toxic, and one can thus employ very large doses without provoking immune reactions, widespread off-target cell death, or other issues. This is a big improvement over past generations of lipid nanoparticles. The DNA machinery carried by the lipid nanoparticles triggers the destruction of cells expressing the tumor suppressor gene p53. It doesn't matter if p53 is mutated and disabled, as is the case in many cancers, as the platform targets the earliest stages of the gene expression of p53, not the presence of p53 itself. The founder shared data from recent studies in immunocompetent mouse models of tumor development, showing that this approach results in a 100% rate of tumor clearance, a substantially better performance than checkpoint inhibitors can achieve in the same models.

Underdog Pharmaceuticals

Underdog Pharmaceuticals is one of the SENS Research Foundation spinout companies. The staff there work on removal of 7-ketocholesterol via the use of carefully designed cyclodextrin molecules that bind to it and carry it to the liver for excretion. 7-ketocholesterol is a form of persistent metabolic waste that has no useful role in the body; removing all of it would be a good thing. This toxic compound is important in the progression of atherosclerosis, but is also probably relevant to a range of other age-related conditions.

Turn.bio

Turn.bio is one of a growing number of groups working on forms of cellular reprogramming to reverse the epigenetic changes and loss of cell function that take place with aging. The Turn.bio approach uses mRNA delivery to achieve partial reprogramming, to shock cells over a few days into reversing their age-related epigenetic changes, without pushing them into abandoning their adult phenotype and function. The company presented gene expression profile data obtained from the use of their therapy in vitro, in which cells exhibited a shift to more youthful phenotypes without changing cell identity. In vivo they have assessed, for example, the impact of their treatment on muscle regeneration, showing lasting improvement in muscle regeneration in aged mice. They are also in the process of assessing delivery of their therapy to the retina to reduce age-related decline in visual function.

Gero

Gero is one of the present crop of AI-based drug discovery groups, using machine learning to speed up identification of therapeutics that might influence aging. They have produced results based on mouse and human data, and have identified a range of drug candidates, largely existing drugs that might be repurposed. They have tested these drugs in mice to assess slowing or reversal of aspects of aging; they view their approach as reducing damage, and think that clearance of senescent cells is probably an important factor in the results they are achieving in mice. The founders are now collaborating with Brian Kennedy in Singapore, and have moved there from their start in Russia.

Nemalife

Nemalife automates the process of screening interventions in C. elegans nematode worms, often used in early stage research in aging. Their product uses microfluidic chips to form a tiny habitat for C. elegans, combined with scanning technology and software, which results in a compact desktop device in which one can run this sort of study cost-effectively. Their differentiator is the small size of their system, which uses lesser amounts of reagents in comparison to other automation for C. elegans studies developed in recent years.

AgeX Therapeutics

Michael West took the floor to talk about about a relatively new subsidiary of AgeX Therapeutics called Reverse Bioengineering, which joins the other companies now working on applications of cell reprogramming. He noted that the cellular rejuvenation that occurs during reproduction, in the early development of the embryo, is the process that inspires these efforts. The AgeX staff are not just interested in changing the state of cells to make them younger, but also in making embryonic and embryonic-like cells older in phenotype. This artificial aging of cell phenotype has applications in producing cell lines and engineered tissues, to ensure that the cells are in the right state for adult function. The company is working on delivery of reprogramming therapeutics via exosomes as well as more traditional approaches. As to why regeneration is turned off in adults versus during embryonic development: the consensus is that this is a cancer risk reduction strategy, selected for by evolution. Cancers exhibit embryonic-like DNA methylation, they represent an inappropriate reversion to embryonic growth and regeneration, but these mechanisms are there to be exploited in a more controlled fashion.

Volumetric

Volumetric commercializes an advance in 3D bioprinting, a system that can incorporate blood vessel networks in the printed tissue that are sufficient to support larger tissue sizes. This has long been the roadblock that prevents serious work on whole organ engineering. This company is indeed aiming at the production of entire organs for transplantation, built from patient cells. They see the roadmap to that goal as starting with 3D printers, then the development of more advanced bioinks, then the creation of small engineered tissue models with complex architecture, and finally the creation of whole organs. Companies such as Volumetric will produce products at each stage that will support this progression; Volumetric is already selling the creation of engineered tissue models as a service.

712 North

712 North is focused on small molecule manipulation of mitochondrial pathways around OPA1, to promote either greater mitochondrial fission or fusion in order to treat specific conditions. More fusion can help some neurodegenerative conditions, while more fission might be the basis for cancer therapies. The company is initially looking at the inherited condition of autosomal dominant optic atrophy, in which there is OPA1 mutation. Looking ahead, OPA1 function changes in Alzheimer's disease in ways that produce results that look similar to those of the inherited condition in the optic nerve. Separately, there is evidence for OPA1 manipulation to reverse tau pathology in mouse models. This all further points to the importance of mitochondrial function in many conditions.

Qalytude

Qalytude is an adaptation of an existing business model for an easy online process to obtain prescription medications. The service uses physician and pharmacy networks to allow people interested in treating aging to obtain metformin, NAD+ patches, rapamycin, the senolytic therapy of dasatinib and quercetin, and so forth. They started with metformin, which I personally think people should not waste their time with, and are moving on to the other options. It is the provision of senolytics to the public at large that is the important part of their program, to my eyes at least. Given a subscriber community, the founders want to expand to conduct studies and gather health data.

Oisin Biotechnologies

Most of the readership here should be familiar with Oisin Biotechnologies, the first company to use the Entos Pharmaceuticals fusogenic lipid nanoparticle suicide gene therapy, in this case to target senescent cells for destruction. They see targeting cells based on their internal patterns of gene expression as the next stage in the evolution of cell targeting: more precise and adaptable than past technologies. The non-toxic lipid nanoparticles can be introduced throughout the body in high doses without side-effects, and the payload only triggers in cells that express p16, a characteristic sign of cellular senescence. The founders showed the full data for the mouse life span study that completed last year, and noted that treated mice didn't just live longer, but also exhibited increased bone density as measured via DEXA scans. They also showed good safety data from a small study carried out in companion animal dogs.

Leucadia Therapeutics

Leucadia Therapeutics works towards reversing the age-related decline in drainage of cerebrospinal fluid through the cribriform plate in the skull. In their model, this is a primary cause of Alzheimer's disease, as it allows metabolic waste to build up in the olfactory bulb where the condition starts. The founder discussed their animal data: they occluded the cribriform plate in ferrets, and as a consequence these animals suffered olfactory bulb degeneration and other aspects of Alzheimer's-like pathology. The company is presently focused on generating large amounts of human CT scan data, to produce an assay that determines who will progress from mild cognitive impairment to Alzheimer's, based an analysis of the state of the cribriform plate. Leucadia will then use the scanned population to determine who will benefit from a small medical device implanted in the cribriform plate to restore drainage of cerebrospinal fluid, and launch a clinical trial.

Repair Biotechnologies

Repair Biotechnologies is the company that I founded with Bill Cherman to work on regeneration of the thymus to address immunosenescence and reversal of atherosclerosis. We are continuing our path of preclinical development. I presented on recent progress in both of these programs, such as mouse data for improved immune function following upregulation of FOXN1 in the thymus, and visualizations of resistance to foam cell formation in a macrophage cell line that expresses enzymes capable of breaking down cholesterol.

Retrotope

Retrotope carries out human studies of treatment with deuterium loaded fatty acids, which are more stable and resistant to oxidative damage than the usual hydrogen-based fatty acids found in the body. The deuterium is very precisely placed - has to be in exactly the right place to avoid toxicity while increasing stability. When delivered as a therapy, replacing a modest percentage of the native fatty acids, these more stable fatty acids greatly reduce lipid peroxidation. The company has carried out clinical trials in an inherited infant neurodegenerative condition, caused by mutation in PLA2G6, and demonstrated reversal of this form of neurodegeneration. PLA2G6 is also implicated in Parkinson's disease, interestingly. The company has run clinical trials in Friedrich's Ataxia patients with good results, and obtained initial human data for progressive supranuclear palsy, showing reversal of the condition in three subjects.

Revel Pharmaceuticals

Revel Pharmaceuticals aims to commercialize glucosepane cross-link breakers based on the work funded by the SENS Research Foundation at the Spiegel Lab at Yale. The candidate enzymes were found via mining bacterial populations for species that can metabolize glucosepane, the primary basis for harmful persistent cross-links in humans. Collagen does not turn over all that much in adults, and these molecules get linked together or have their structure detrimentally altered via glucosepane cross-links. Cross-links accumulate steadily over time, from age 20 onwards, rising to pathological levels in later life. The founder noted that there have been trials of cross-link breaker small molecules in the past, but as of yet there are no successfully approved products.

Maia Biotechnology

Maia Biotechnology produces what they term telomerase-mediated therapeutics to target telomeres. This is perhaps the first group to attempt commercial development of a near universal cancer therapy based on suppressing tumor growth via interfering in telomerase and telomere function in cancer cells. They have developed a DNA sequence called THIO that, once introduced into cells, is incorporated into telomeres by telomerase activity. THIO sabotages cell function once present in telomeres, causing cell death. The founders presented in vitro data showing cell death in various cancers cell lines when exposed to THIO. THIO also combines well with PD-1 checkpoint inhibitors, when tested in mouse models of cancer, producing much better results than either on its own - actually completely clearing the tumors.

Comments

"Leucadia will then use the scanned population to determine who will benefit from a small medical device implanted"

I wish things could progress faster.

If you have Alzheimer's, what do you have to lose by trying the device? In an unregulated world, it should not take more than a year to determine if the device works or not.

Posted by: Peter Lind at January 20th, 2020 1:35 PM

@Peter Lind

Mind that if one is in a late stage, it might not work because of the damage processes going to far, even if the approach as a whole is correct.

Posted by: Cuberat at January 20th, 2020 2:25 PM

@Reason

Did OISIN show more details on their study!

Posted by: Cuberat at January 20th, 2020 2:31 PM

@Cuberat: The life span study? Yes, as I mentioned. It progressed through much as one might expect given the earlier life span study, a similar ballpark of outcome.

Posted by: Reason at January 20th, 2020 2:48 PM

A very interesting overview. I'm intrigued by Maia. How do they target their DNA sequence to cancer cells specifically? Or is it like chemo and targets all actively dividing cells?

Posted by: Antonio at January 20th, 2020 4:18 PM

I'm very interested in Qalytude, specially regarding the case of fisetin. On next June, Mayo Clinic will release Phase 2 Clinical Trial Results of fisetin, and if these results are considerably positive, it would mean that a cheap, relatively safe and effective senolytics are at disposal of people in general. However, for the public at large, there would still be some barriers, and to explain them - and how Qalytude could help - I will give my example. My parents are 72 and 73 years old (the age range of the Mayo Clinic clinical trial). They (and I) live in Brazil.
The first problem is that in order they could follow the Mayo Clinic protocol, they would need to be sure that the fisetin they would get is of a good quality. They could buy it from Amazon or something like this, but it's necessary more safety than that, it seems to me. So it would be awesome if a company with the confidence of big names of rejuvenation area (like FightAging!, SENS Research Foundation, etc.) could proportionate the fisetin, and send it to other countries, like Brazil. I entered Qalytude website and I saw that they mention, besides FightAging! and SRF, BetterHumans, Age Reversal Network and LEAF, as organizations they support.
The second problem is that it would be important that some entity (like Qalytude) could, besides providing the fisetin, explain how to take it (it should be mixed in a glass of water? Or it should be taken in pills? This kind of things). This is important in terms of practicity.
The third practical hurdle is the fact that, despite it (I hope) would have been tested and approved in Mayo Clinic, it's a new treatment, so a medical supervision in the day it's taken would be very helpful, even if it is online. For example: if my parents take fisetin, and, let's say, their temperature increases a little 2 hours later, I would like to be able to ask a doctor if it is all right, if this is common, etc. Also, in advance, it would be good to know what side effects could appear, like headache. So, for example, Qalytude could proportionate a service like the following: the client order the fisetin from Qalytude, Qalytude indicates how to take it, and the client schedules a day with Qalytude to take the fisetin. In that day, even if the fisetin is taken in another country, Qalytude will indicate a doctor who will be available online (like in WhatsApp) for the case that something strange happen in the hours after taking the fisetin. So, if, for example, my parents are not feeling well after taking the fisetin, I would want to ask what to do to someone who knows about fisetin, and not to a doctor here in Brazil who never heard about fisetin, senolytics, etc. Of course, all this depend on the Mayo Clinic Results of Phase 2 Trials, but if Qalytude proportionates this, they could have a big market, and they would extremely useful for many people. So, basically, they would need proportionate three things: the fisetin, an explanation of how to use it, and an online doctor in the day the fisetin is taken.

Posted by: Nicolas Chernavsky at January 20th, 2020 9:51 PM

Definitely a lot more companies to talk about last year. And a lot more companies that are focused on damage repair, rather than trying to let people live longer with a damaged metabolism. Lets hope this trend continues.

I wonder what the next SENS spin out will be?

Posted by: jimofoz at January 21st, 2020 5:27 AM

Ref: Qalytude and fisetin

In the USA, fisetin is an over the counter supplement. Qalytude is a new business in the USA trying to be profitable selling services for off label use of prescription drugs, specifically for anti-aging. Qalytude makes it easier for USA residents to get these prescription drugs.

They have doctors licensed to practice in the USA. It would be a big leap for them to serve people outside the USA.

IMHO, your parents would be better off coming to the USA and go to a licensed ant-aging doctor.

It is still more or less the wild west comcerning anti-aging protocols. Very few medically approved human studies have been done yet.

Posted by: David Hanson at January 21st, 2020 7:03 AM

@Reason
In your summary of the OncoSenX presentation you said the following " the platform targets the earliest stages of the gene expression of p53, not the presence of p53 itself". What does this mean exactly? It would seem that one leads to the other. If P53 is being expressed in noncancerous cells in any significant quantity, how is OncoSenX achieving the necessary differentiation between cancerous and noncancerous cells?

Posted by: Rick Davis at January 25th, 2020 2:32 PM

@Rick Davis: The point is that any effort to key a therapy against the presence of p53, meaning specific sequence or characteristic of the transcript or the protein, will likely fail in cancer tissue because of mutations that lead to a different, non-functional p53 protein.

Posted by: Reason at January 25th, 2020 2:46 PM

@NicolasChernavsky Fisetin with water? Dump it directly into WC, the effect will be the just the same but without a hassle of taking it. It's practically unsoluble in water. The main food source, strawberries (Fragaria ananassa) is consumed with dairy products with high fat content for best sollubility. For raw fisetin tah it the same with fat dairy product or olive oil. Prostate is the best fisetin detector, after doses >0,5 gram your sperm becomes citrus yellow (natural light) or green-yellow (fluorescent light). So you don't need any laboratory to confirm quality and content of fisetin in a supplement. The common US supplement brand sells it for 13$/3gram (a one dose for 100kg man). I observed some visible effects on wrinkles starting at doses of 2,5g (per 102 kg of weight), but I took it with quercetin and resveratrol (Q+R show week anti obese effect of changing white fat into brown fat, but adding fisetin greatly enahnces bioavailability for all three, up to 5 time for resveratrol, 4x for quercetin and 3x for fisetin). Cotinus coggygria is the main source, it could be used as low as 50% but cause a bit of diarhera at these doses. >95 pure fisetin cause no stomach symptoms. Accacia gregii also utilies this yellow pigment, and after germans imported it into europe it is a common weed now around. As osteoblasts multiply faster that you would suspect supplemneting with calcium and magnesium it's a must. Only after 2 months calcium level drops considerably. And take high caution if you have history of tendrils injuries. I managed with a calcium and Bioptron lamp, but some others reported they had to resort to strong pain killers to menage pain.

Posted by: SilverSeeker at January 27th, 2020 6:27 AM

@NicolasChernavsky CAUTION: accacia is poisonus, so it can't be consumed without a chemical facility to purify fisetin out of it (the same for Rhus succedanea, that's why they refine fisetin to 95%-98% purity from it). Coggyria is not poisonus, can be consumed as herb just raw for short periods, but fisetin content is too low to get senolytic dose this way. So purification is also needed. Strawberries with 160mg/kg the same, to eat 20kg (+ plus dairy products or fats to dissolve it) at once is definitely impossible.

Posted by: SilverSeeker at January 27th, 2020 7:04 AM

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