Fight Aging!

The former Longevity Therapeutics conference series was renamed to the Age-Related Disease Therapeutics Summit and held its fifth event recently in San Francisco. It was a smaller meeting than in past years, perhaps a result of the recent downturn in the global financial and investment environment. Few investors were present. Nonetheless, one can usually learn something interesting from the presenting biotech founders and executives. I took a few notes while I was there to present on progress at Repair Biotechnologies, and they follow in the order of the conference program.

Birget Schilling from the Buck Institute for Research on Aging discussed the role of cellular senescence in bone aging. She focused on techniques for discovering signatures of aging in human bone tissue, looking at protein expression and composition of the bone extracellular matrix. This included the use of bone organoid models derived from patient cells and patient tissue samples. This was a snapshot of early-stage investigative research, some distance from any preclinical development and application to medicine.

Abdlkadar Rahmo from SMSbiotech, a cell therapy company, presented on the merits of in vitro human cell and tissue models of aging. Using such models can be cost-effective, but there are of course meaningful differences between an in vitro model and tissue in a living organism, and a great deal of work remains to be accomplished in standardization and reliability. The primary focus was on organoids derived from patient tissue samples, and a number of different models were described, including skin, brain, and intestinal structures. The company works on a specific type of adult stem cell found in human tissus that they call small mobile stem (SMS) cells. The company uses these cells in the manufacture of cell models, as SMS cells readily produce extracellular matrix that encourages blood vessel formation.

A panel discussed how to better improve translation from animal models to humans, always a challenge in every field. The general sentiment was that greater use of human organoids enables a more rapid process of fundamental discovery, skipping over animal studies until later in the process. It remains challenging to match animal models to diseases sufficiently well to avoid issues, and the field is littered with models that may be too artificial to be useful, but finding out that this is the case is a lengthy, expensive process. Making animal models better is a tough problem, and it was suggested that use of human organoids will at some point take over from that project. It was also suggested that gene therapies make animal models more useful, as there is a greater known consistency in the way the therapy interacts with animal versus human biochemistry.

Adam Kaplin of MyMD Pharmaceuticals presented on their inhibitory molecule that targets TNF-alpha and other important cytokines in inflammation and oxidative stress. Treatment dials down chronic inflammation in age-related disease and autoimmune disease. It is presently in clinical trials for sarcopenia and rheumatoid arthritis. Some of the fine details of the cytokine profiles following dosing were outlined. They believe their molecule is somewhat more selective for excessive inflammatory signaling versus needed inflammatory signaling than is the case for earlier inhibitors, which is an important issue in this part of the field. They demonstrate in mice that this inhibition of excessive inflammation can slow aging meaningfully, improving function and reducing mortality to a greater degree than rapamycin.

I presented on recent progress at Repair Biotechnologies. We develop a gene therapy, lipid nanoparticle delivery of mRNA, that can selectively clear excess intracellular free cholesterol. Our latest data shows sizable, rapid, safe reversal of the pathology of NASH in mouse models of the condition. We can also reverse atherosclerosis, removing plaque lipids in the same rapid, safe manner in animal models. We aim to conduct our first pre-IND meeting with the FDA later this year, and thereafter work towards an initial clinical trial in humans.

Peter Fedichev of Gero presented on their analysis of aging and disease. They make extensive use of machine learning to produce insights from large longitudinal data sets, both animal and human. Their view is one of regulatory systems and disturbance of homeostasis, a growing instability in regulation of complex processes in the body. Mice are less stable than humans, less resilient to disturbance of homeostasis, and a longer species life span might be considered a matter of better maintained stability. Gero tests a variety of approaches known to slow aging in mice in the context of their computational models for regulation of aging, seeking a better understanding of how exactly these treatments act on the body. From analysis of human data they identify a point of regulation and potential therapeutic, then confirm in mice, and thereafter hope to bring their best candidates into human trials.

Robin Mansukhani of Deciduous Therapeutics presented on their approach to clearing senescent cells via adjusting behavior of the immune system. They are advocates of the view that the growing burden of senescent cells with age is primarily an issue of immune dysfunction, though this is a multifaceted failure in many different immune cell types and recognition processes. The company is focused on natural killer T cells, and use small molecules to provoke these immune cells into more actively recognizing and destroying senescent cells. A single dose produces lasting improvement in senescent cell clearance, retraining aged immune cells into greater activity. Deciduous uses this approach to therapy to treat pulmonary fibrosis and type 2 diabetes, both conditions associated with cellular senescence, and are working towards clinical trials.

Doug Ethell of Leucadia Therapeutics discussed progress towards a small implantable device, essentially just a sensor-controlled valve, that restores cerebrospinal fluid drainage through the cribriform plate behind the nose. The company's preclinical evidence, including imaging of a large human study population and studies in ferrets, support a role for impaired drainage through the cribriform plate in the early development of Alzheimer's disease. The channels of the cribriform plate ossify and close with age. Without efficient drainage, metabolic waste of all sorts, including extracellular amyloid aggregates, accumulates in the brain, and this leads to neurodegeneration. At this point, the company is a year or so away from initial human trials of their device.

Michael Fossel of Telocyte started by outlining a view of aging as a growing imbalance between dynamic, constantly active processes of (a) damage and dysfunction versus (b) repair and restoration. This led to a discussion of changes in average telomere length as an important feature in tissues in aging, while noting that measuring telomere length in leukocytes from a blood sample is uninformative as to the state of the body. In this view, extending telomeres with telomerase expression is not targeting a cause of aging, but it is intervening at a convenient point in the processes of aging to adjust cell behavior for the better, restore more youthful epigenetic patterns to some degree, and improve tissue function. The company currently has unnamed sources of sufficient funding to conduct clinical trials of telomerase gene therapy as a treatment for various diseases of aging including Alzheimer's disease, but the timeline is unclear.

Jerry McLaughlin of Life Biosciences focused on their efforts in the hot field of partial reprogramming. They use an OSK cocktail, leaving out MYC from the original Yamanaka factors in order to prevent dedifferentiation and tumor formation. This approach, as with other reprogramming approaches, can reverse the characteristic epigenetic changes associated with aging, producing rejuvenation. They deliver an AAV carrier with a payload of conditionally activated OSK, only expressed in the presence of doxycycline. Their target indications for the clinic involve retinal damage and aging, as the eye is an isolated site and a good target for AAV gene therapies. They presented recent positive data on treatment of optic neuropathy in a non-human primate, resulting from ischemic damage in the retina. The treated primates showed a lesser loss of a measure of visual function, and exhibited improved survival of axons in the retina. The company is aiming for an initial clinical trial to start in late 2024.

Louis Hawthorne of NaNotics outlined the basis for their technology, a silica nanoparticle decorated with binding agents and covered by a shield layer that can efficiently remove specific molecules from the bloodstream without interacting with cell surfaces. Essentially a programmable sponge, and much more effective than antibodies. Mounting evidence points to various signal molecules in the bloodstream that increase in amount with age as contributing to various age-related diseases. One might consider pro-inflammatory cytokines, for example. Some groups have used expensive plasmapheresis to remove specific inflammatory molecules with good results, such as soluble tumor necrosis factor receptors (sTNFR) removal in the treatment of cancer, and NaNotics aims to do much the same thing more effectively. PD-L1 is another oncology target, and the company are moving to human trials in 2024 on the strength of a Mayo Clinic collaboration.

James Peyer of Cambrian Bio painted an interesting picture: that the challenge for our field is not that we cannot run trials for aging, nor designating aging as a disease, but that geroprotective drugs as a class of therapy require preventative trials for multiple comorbidities that are too lengthy to be economically viable in the current regulatory framework, given the venture capital mindset on duration of funds and need for return in a given timeframe. Thus we need to build new types of long-term research and development organizations, ones with sufficient funding to run multi-disease prevention trials over a longer timeframe than is presently possible. This way of thinking about the market is how Cambrian Bio came about, a well-capitalized entity intended to take programs all the way from academia through to these long clinical trials. Cambrian Bio has a sizable number of subsidiary biotechs, mostly stealth mode. Peyer talked about one of them, Telos Biotechnology. The company is focused on the ability of telomere lengthening to improve the performance of CAR-T cells in cancer therapy. The hypothesis is that current challenges in producing sufficient numbers of CAR-T cells for older patients has a lot to do with shorter telomeres and thus more replicative senescence during expansion in culture. The resulting cells are also less effective. The company develops an approach to increase telomere length in these CAR-T cells during expansion in cell culture, making a big difference in the cost-effectiveness and efficacy of CAR-T therapy.

Lorna Harries of SENISCA discussed progress on a platform for adjusting age-related dysregulations in RNA processing, such as altered RNA splicing resulting from changing expression of splicing factors, in order to suppress the burden of cellular senescence. Restoration of lost splicing factor expression can prevent and even reverse cellular senescence. Interestingly it also repairs some of the DNA damage characteristic of senescent cells. (This doesn't work in oncogene-induced senescence, where there is catastrophic DNA damage). To achieve this goal, the company uses a portfolio of oligonucleotides that can alter expression of various splicing factors and their regulators. The company is initially targeting idiopathic pulmonary fibrosis, as are many groups that work on clearance of senescent cells, and showed in vitro data in cells taken from pulmonary fibrosis patients, demonstrating restored markers of cell function. They have similar data for other cell models of age-related diseases connected to cellular senescence, such as cartilage degeneration.

Marco Quarta of Rubedo Life Sciences presented on the poorly catalogued differences that exist between senescent cell types, by origin and tissue type. It seems unlikely that any one small molecule senolytic would be able to effectively target all senescent cells. Chemotherapy and checkpoint inhibitor survivors exhibit increased senescent cells and reduced quality of life, but different chemotherapies apparently produce different states of cellular senescence, with varying vulnerability to specific senolytic drugs. So it may not be as straightforward as hoped to use senolytics to prevent lasting side-effects of cancer treatment. This example extends into other conditions and origin of senescence. Thus the company works on a big data, machine learning platform to identify senescent states associated with specific tissues and conditions, and then screen new senolytic small molecules tailored to these senescent cell states. They are aiming for an initial clinical trial in 2024.

Viktoria Kheifets of Alkahest discussed the current state of the art in altering levels of specific blood factors in order to suppress detrimental metabolic changes characteristic of aging. Alkahest is owned by a large medical-industrial blood plasma organization, acting as a research arm that can develop new commerical uses for its products. They see blood plasma as a master communication highway, transferring information between cells throughout the body. The company presently undertakes a great deal of data collection and analysis of the contents of blood samples in various ages and conditions, identifying clusters of various molecules and matching them to phenotypes. They then conduct studies in mice to see if plasma fraction transfusion can produce meaningful therapeutic benefits by altering specific plasma molecule levels. It is unclear as to which of the current preclinical programs will in fact be taken forward to the clinic, as this depends on the slow economic calculations of the large owning company. One interesting item is that the company has tried delivery of only albumin into old animals, and have seen no meaningful benefit. You might recall that there is some question over whether dilution of plasma works to improve health because albumin is delivered with the saline, and the result depends on replacement of existing, perhaps age-damaged, albumin. This may not be the case, and it is really the dilution of other harmful factors that causes improved health.

Szilard Voros of G3 Therapeutics talked about efforts to use big data analysis, of omics and epidemiological databases of thousands of individuals assessed over time, to rationally design entire clinical programs targeting age-related diseases, from the mechanistic target through to predicted odds of success of a clinical trial of a small molecule targeting that mechanism. The company has built a vast set of data, down to the level of expression patterns in specific tissues, and uses that data to move therapeutics towards the clinic.

Andrei Gudkov of Roswell Park Cancer Center presented a contrarian position on senescent cell biochemistry. Researchers used a mouse model which they lethally irradiated and then rescued by replacement of bone marrow, expecting greater cellular senescence and accelerated aging, but while the mice had a 20% shorter life span, their late life frailty was actually reduced in comparison to controls. Oddly, these mice also exhibited no sign of increased cellular senescence using traditional biomarkers such as P16 and inflammatory signaling. Their conclusion was that most P16 and SA-beta-gal expressing cells in old tissues that are pumping out inflammatory cytokines are actually macrophages, not what are presently thought of as senescent cells. Strangely, mesenchymal cells of these irradiated mice immediately become senescent when put into culture and forced to divide, while remaining non-senescent and non-dividing in vivo. Also the mice have impaired wound healing and excessive appearance of senescent cells in injuries. Further, if they are given a high fat diet grow fat, then they exhibit raised mortality. This is all connected to cell proliferation. The implication is that the mice have genotoxic stress due to radiation-induced DNA damage, but this dormant harm is only realized when cells are forced to proliferate. This all says something interesting about how senescence and DNA damage interact, that damage can remain dormant, a potential for senescence to be realized later.

A panel discussion focused on choice of biomarkers as important in achieving success in clinical trials. When setting up a clinical trial, one has to convince the regulators that the proposed biomarkers are appropriate. A poor choice, whether it originates with the company or the FDA, can doom a trial even if the therapy actually works. Biomarkers might be (a) predictive, in the pre-disease state, though few clinical trials are conducted for prevention, or (b) diagnostic to establish the state and progression of established disease. One also needs easily measured biomarkers that determine the degree to which the therapy is active in a patient. In the best of worlds, these choices are obvious and straightforward. But it is rarely that simple, particularly in the matter of aging or new mechanisms of action.

Joshua McClure of Maxwell Biosciences presented on the company's broad anti-inflammatory platform derived from innate immune system antimicrobial peptides, which is progressing towards clinical trials. These factors were discovered using big data analysis of heterochronic parabiosis studies, looking at old and young blood and comparative omics profiles. The company has taken the non-dilutive funding approach to fundraising, and has been largely funded by government research grants rather than venture capital. Their primary candidate molecules are derived from LL37, a ubiquitous antimicrobial peptide that appears to have a range of other helpful, protective functions both connected and unconnected to immune function. The preclinical data is quite impressive, and this therapy may go on to improve outcomes in many infections, cancers, and other conditions.

Hans Keirstead of Immunis presented on their approach to culturing stem cells in order to produce a secretome as a drug that can improve immune function, reducing immunosenescence and inflammaging. This manufacture isn't as easy as it might sound. Standardization of any sort of product that involves cell populations is a challenge. That it is hard and expensive and failure-prone to manufacture cell therapies is a large part of why there is strong interest in moving to cell secretions as a basis for therapies derived from what we know about how cell therapies influence tissues. It is easier to control cells in a dish to produce a secretome that can be assessed on ~10 marker proteins than it is to produce cells for transplant. Delivering a secretome to improve immune function to mice produces a wide range of benefits, and the hope is that enough of this will translate to humans to succeed in clinical trials for indications that have traditionally been targeted for the development of stem cell therapies.

Hanadie Yousef of Juvena Therapeutics discussed their approach to therapy. The company has used proteomic analysis of secretomes from various cell types known to promote regeneration in order to identify regulatory molecules that are enriched in scenarios of regeneration. They use machine learning based on the library of proteins they created in order to predict which secreted molecules are likely to be useful for given indications. They then engineer improved versions of these proteins. Their lead protein is at the pre-IND stage, initially to treat a form of muscular dystrophy, and they hope to start clinical trials by the end of 2024.

David Furman of the Buck Institute for Research on Aging talked initially about a project to build a large omics database of human imune aging. This data led to an unbiased search for makers of inflammaging, which lead to the inflammatory age (iAge) clock. This clock correlates with health outcomes and mortality, as one might expect given what is known of the role of inflammation in aging. A company and drug discovery program resulted, and various candidate drugs that reduce iAge have been tested in human trials. The presentation moved on to the use of accelerated aging models to make studies run more rapidly. This specific effort involves the apparent acceleration of aging that occurs as a result of time spent in microgravity. A company, Cosmica, to run drug discovery programs targeting mechanisms of aging more rapidly than is usually possible based on this class of accelerated aging, using organoids in a microgravity environment, with human astronaut data for validation. Perhaps the most interesting point here is that measures of accelerated aging in astronauts reverse once back on the ground again, and one might ask: what are the driving biological mechanisms of that restoration? The company believes that the primary mechanisms they are observing are related to cell mechanosensing of the extracellular matrix, and microgravity disrupts this in ways that somewhat mimic some of the biochemistry-driven issues with cell/extracellular matrix interaction that occur in aging.

Noah Davidson of Rejuvenate Bio discussed progress towards the clinic for their leading gene therapies. They use AAV as a vector platform, and intend to take its use beyond the present correction of rare genetic disorders into a broader set of age-related conditions. They are primarily focused on cardiac disease, picking genes and mutations that have been shown to extend life in mice and that will address specific issues that occur in cardiac diseases, such as fibrosis and mitochondrial dysfunction. They screened combinations of upregulation and downregulation of various genes, and settled on the current favored combination of FGF1 and anti-TGF-beta-1 - increasing FGF1 expression and decreasing circulating TGF-beta-1 using a binding receptor fragment. They have been using the therapy in companion dogs for a few years, with a good safety profile. A single treatment is expected to last for a decade or longer, but the expression is inducible; it requires taking a pill daily to activate expression of the therapeutic genes, for an additional layer of control of the therapy. The company aims to expand out into a broad veterinary market for dogs, and thus will provide supportive data for clinical development of the same class of therapy for human use.

A panel discussed how aging-focused biotech companies might better build bridges to large pharma entities, which are typically slow to engage meaningfully with any change in the state of the science and the industry. This quite quickly turned into an exchange about the various groups that are trying to circumvent the established regulatory environment, and build alternative paths to clinical application and revenue. It seems clear that many people in the longevity industry as it stands put pharma entities in the same category as regulators: a mountain that lies ahead, an unpleasant but necessary task of engagement if one is to play the game as the rules are written. The conversation then moved on to the power of data. A truly curative, impressive therapy will shape the system around it, and will find a way, the obstacles will melt away. In the matter of aging, the biggest challenge is how to measure such an impressive therapy in order to prove that it is in fact impressive in something less than a decade-long study.

Alexander Picket of Juvenescence talked about a drug development program leading on from the discovery of a small population of humans with a loss of function mutation in PAI-1 and who appear to exhibit a longer life expectancy as a result, an additional seven years. This gene lives at the border of immune function and fibrinolytic system responsible for clotting, and has a lot of activities beyond that. It touches on cellular senescence, for example. There was some discussion of how, even given this very obviously interesting mechanism, and a drug that replicates the effect to some degree, it is still complicated and hard to find a way through the regulatory system as it exists today. A lot of this involves downstream effects of government regulation of medicine, insurers, and medical pricing, as at the end of the day the large funding sources will only invest in clinical trials for drugs wherein a profit can be made, and regulation ensures that many types of treatment simply cannot be profitable in any of the ways they are permitted to be deployed.

Pankaj Kapahi of the Buck Institue for Research on Aging discussed glycation in aging. Advanced glycation endproducts (AGEs) produce a number of issues, such as inflammation due to interaction with receptors and the reaction of the immune system to glycated proteins, and also cross-linking in the extracellular matrix. This is most evident in the sugar-heavy dysfunctional metabolism of diabetics, but in aging it seems likely that persistent AGEs also generate meaningful pathology. The research here focused on methylglyoxal, a precursor of AGEs. Scientists found a way to reduce methylglyoxal levels in the body using a cocktail of supplements. This led to a spinout company Juvify Health and a supplement product. In mice this improves insulin metabolism and reduces body weight in addition to achieving the expected biochemical measures such as degree of glycation of proteins. The body weight change appears to be because targeting AGEs in this way suppresses hunger mechanisms, and the mice eat less, which is an interesting finding.

The theme for the industry at this time appears to be that many clinical trials of novel therapeutics targeting mechanisms of aging will start up in the next few years, assuming funding can be found. Impressive data tends to attract that funding. Market downturns don't last, and the next boom period will be characterized by the advent of a range of methods to greatly enhance immunity, slow aging, and turn back specific age-related conditions presently resistant to treatment. Interesting times!