Reason to Repair
Part 2 of a series on the mission to defy aging
If you’re a Game of Thrones fan, you know that in The House of Black and White, there resided for a period of time a girl with no name. What you may not know is that at the forefront of anti-aging technology, there resides a man with only one name — Reason.
An astrophysicist focused on anti-aging…time travel not involved…
Reason started out as an astrophysicist of all things. That left me scratching my head. My mind became filled with images of H. G. Wells fading in and out of focus. I imagined some modern version of a time machine. But I couldn’t have been more wrong.
You see, one day Reason awoke and decided that he didn’t want to die. He characterizes that moment as “something of a revelation,” which “set the course of his life from that point on.”
Since Reason needed to know how to code for astrophysics, he wound up with a career in software engineering. But, in the evenings and often the wee hours of the night, Reason read everything he could about longevity and rejuvenation biotechnology. That dual life continued for more than 20 years.
Reason points out that astrophysics, as a field of study, “actually has a lot in common with medical biotechnology — the vast scope of the unknown compared to what is known, for one.”
And, while he read and learned, he published commentary on the latest research. According to Reason, “it was a lot of work for me to figure out what was being done, what was possible, and who was talking sense or nonsense, and I wanted to make that process of discovery and comprehension easier for other people.” It was a way for him to give to the community, while educating himself at the same time. If you would like to see the fruits of his labor, go to www.fightaging.org.
So, not unlike Buddha sitting under a Bodhi tree, Reason became increasingly enlightened. Over time, he found himself gravitating towards approaches that he believed were plausibly going to have a significant impact on human aging — such as the SENS (strategies for engineered negligible senescence) initiative by Aubrey de Grey, one of the co-founders of the Methuselah Foundation (click here to learn more). His posts on fightaging.org followed the same course. And he argued for a focus on rejuvenation research after the SENS model.
Reason’s altruistic advocacy naturally evolved into helping non-profit initiatives, raising funds for research, investing in start-up companies, and starting his own company. This trajectory was influenced by progress in research, increased support for the cause, and the emergence of longevity as an industry. Reason says, “It all sounds very straightforward now in hindsight, but it has been a long road. It was initially very challenging to find support for the idea of treating aging as a medical condition. The growing longevity industry that we see today is very much the result of a great deal of thankless toil on the part of advocates over the past twenty or more years.”
Repair Biotechnologies
And so, in 2018, Reason co-founded Repair Biotechnologies with Bill Cherman, who has a background in investing in biotech and blockchain. Reason met Cherman in the course of discussing the few companies inhabiting the longevity space at the time. Reason says, “We talked about what we might do that was more helpful than merely investing, and of the ideas, starting a biotech company was the one that seemed the most likely to produce meaningful advances in the state of medicine at the end of the day.” According to Reason, “The angel investment community associated with rejuvenation research was small and close-knit — and comprised of people who were more interested in advancing the state of medicine towards human rejuvenation than in making money. Funding companies was merely a more efficient path forward than funding academic research at the time.”
And Reason and Cherman were strategic in focus. They wanted to undertake projects in areas that Reason says “(a) have a very large, positive impact on human aging and mortality, (b) have a high likelihood of success based on the research results to date, and (c) are not advancing rapidly enough towards clinical translation for our liking. Thymic regeneration and reversal of atherosclerosis were some combination of near the top, ready to go, and possessed of very compelling data from the research community.”
Before delving into thymic regeneration, here’s some background on the thymus.
The Thymus — 101
The thymus is part of the immune system. It is a small, bi-lobed organ that is located behind the sternum, between the lungs. It has two layers — an outer cortex and an inner medulla. The thymus produces the hormone thymosin. Thymosin stimulates the development of T cells. T cells defend the body against infection and cancer.
T cells are derived from hematopoietic stem cells — immature cells that can develop into all types of blood cells — found in bone marrow. The stem cells migrate from the bone marrow to colonize the thymus. Once there, they are referred to as thymocytes. Thymocytes undergo a series of maturation steps to become T cells.
Cells at different stages of maturation can be distinguished by markers on their surfaces. Initial steps of maturation take place in the cortex. In the cortex cells undergo positive selection for interaction with foreign antigens. Those that interact weakly die. The remaining cells then migrate to the medulla, where they undergo negative selection for interaction with self-antigens. Those that interact strongly die. The cells that survive positive and negative selection undergo further changes and then leave the thymus to circulate in the body.
The thymus is at its largest size (about 1 oz.) in children. Once children reach puberty, however, the thymus starts to shrink (i.e., atrophy). Over time, it is replaced by fat.
The thymus can also be damaged. For example, a chronic infection, a medical procedure, or a genetic condition can damage the thymus. Examples of medical procedures include chemotherapy and radiation therapy. An example of a genetic condition is DiGeorge Syndrome, which results in a small or missing thymus.
If the thymus doesn’t work properly, immunodeficiency or autoimmunity can result. Immunodeficiency is when there aren’t enough T cells to protect the body against infection and cancer. Autoimmunity is when T cells attack the body, itself, instead of foreign agents (e.g., bacteria, viruses, and fungi) and cancerous cells.
Indeed, thymic involution is one of the most important factors contributing to the reduction of the immune response with age. There is a steady decline in the production of undifferentiated (“naïve”) T cells that can differentiate into T cells that can counterattack new invasions of foreign agents. This is accompanied by an increased risk of severe infection (for a recent review, see Zdrojewicz et al., “The Thymus: A Forgotten, But Very Important Organ,” Adv. Clin. Exp. Med. 25(2): 369–375 (2016)).
Current therapies for the thymus
Administration of a protein called interleukin-22 (IL-22) can help a thymus that has been damaged by chemotherapy or radiation therapy. Human growth hormone (hGH) has been shown to enhance recovery of the thymus. Pre-clinical data also suggest that interleukin-7 (IL-7) may help as well. Other studies indicate that inhibiting production of sex hormones — chemically or surgically — can promote growth of the thymus.
DiGeorge Syndrome can be treated by transplantation. Currently, only pieces of thymus obtained during heart surgery in a very young patient can be used for transplantation.
But Reason and Repair Biotechnologies have focused their attention on FOXN1. As Reason explains, “The thymus, while being very inconveniently placed in the body, is nonetheless a convenient organ to work with in the sense that it has one master regulator gene that governs growth and activity: FOXN1.”
FOXN1
FOXN1 is an acronym for the ForkheadBox N1 gene or the Winged-Helix Transcription Factor Nude gene (among others). When this gene is mutated in mice and rats, the animals are hairless and lack the thymus gland. The result? A severely compromised immune system.
The FOXN1 gene encodes a protein that is a transcription factor. The transcription factor binds to DNA and controls which genes are transcribed into mRNA, which, in turn, is translated into protein. Thus, FOXN1 regulates the development, differentiation and function of cells in the thymus — and, ultimately, the production of T cells.
Studies published from 2010 through 2016 have shown that overexpression of FOXN1 in mice regenerates active thymus tissue. T cell production increases, and immune function improves. Also, a phase I clinical trial led by Greg Fahy showed that administration of hGH and DHEA (dehydroepiandrosterone — a hormone produced by the adrenal glands) safely reversed thymic involution.
Thymic regeneration
Reason and Repair Biotechnologies wanted to take an approach to thymic regeneration that increased efficacy and reduced, if not eliminated, side effects. And they decided on a gene therapy approach. In Reason’s words, the approach being used by Repair Biotechnologies is “a modern gene therapy platform that overexpresses FOXN1 in the thymus in a lasting manner, ensuring that the organ regrows the active tissue responsible for maturation of T cells, and that this tissue is, in fact, as active as it can be.”
The expectation is that the therapy will be delivered by intravenous injection. As for the outcome? An enlarged thymus, which produces more naïve T cells. And more naïve T cells leads to more differentiated T cells that can counterattack invasions of new foreign agents.
So far, Repair Biotechnologies has demonstrated that their gene therapy approach increases human FOXN1 (hFOXN1) mRNA and protein levels in thymic epithelial cells. They have also demonstrated increased hFOXN1 and murine FOXN1 (mFOXN1) mRNA and protein levels in old mice. Initial results also appear to indicate increased levels of T cell populations (CD3+, CD4+, and CD8+).
Next steps for thymic regeneration
As for what’s next, Reason says, “Next is more of the same: having demonstrated that we can do this with our gene therapy, we now do it again with many more mice, more robustly, and with much more assessment of the results. Thereafter we will move towards finalizing the most effective formulation for our therapy, and then ready it to enter the FDA IND (Food and Drug Administration Investigational New Drug) process. This will take place over the next year or so.” Currently, the company is focused on cancer as an indication — particularly in conjunction with checkpoint inhibition (inhibiting the tendency of the immune system to “put the brakes on” when fighting cancer cells). Reason is quick to point out, however, that “restoring function in the aged immune system might be applied to, say, vaccination in the elderly, recovery of immune function in HIV non-responders or HSCT (human stem cell therapy) patients, or frailty.”
Repair Biotechnologies vs. the competition for thymic regeneration
When asked about the competition, Reason responds, “Intervene Immune has produced human data for a lengthy growth hormone treatment. Lygenesis is producing thymus organoid tissue for implantation into lymph nodes.” He believes that Repair Biotechnologies’ approach “should be much more efficient and have a larger effect size.” And, in addition to obviating the need for surgery, Reason points out that Repair Biotechnologies’ approach “also bypasses any questions there might be as to whether or not thymus organoids are going to produce the correct distribution of T cell types, or otherwise act in the same way as the natural thymus.”
And now, before turning to the reversal of atherosclerosis, here’s some basic information about the disease.
Atherosclerosis — 101
Atherosclerosis is a disease of the arteries. The disease can be caused by high blood pressure, smoking, or high cholesterol. Atherosclerosis begins with damage to the endothelium — the thin layer of cells lining the vessels. Then bad cholesterol or low-density lipoprotein (LPL) crosses the damaged endothelium. When this happens, a plaque of fatty material forms. The plaque results, in large part, due to the presence of white blood cells known as “macrophages.” The macrophages try to get rid of the plaques. The problem is that they don’t do a good job, and their presence only contributes to the problem. The plaques lead to hardening of arterial walls and narrowing of their internal channels. Both these conditions adversely affect blood flow. Heart attack, stroke, and peripheral vascular disease can result. Heart attack and stroke occur when a plaque ruptures and causes blood to clot.
Current therapies for atherosclerosis
Apart from making lifestyle changes to reduce risk factors (e.g., smoking, high cholesterol, high blood pressure, diabetes, abdominal obesity, stress, and excessive alcohol intake), medication — typically a drug that reduces LDL-C (or bad cholesterol) — is often prescribed. With medication, plaque growth may slow or even stop. In some instances, with aggressive treatment, plaques may shrink slightly. A daily low-dose of aspirin can help reduce the risk of clot formation. Angiography (live x-ray screening) and angioplasty (catheter with a balloon tip) or stenting can be used to open blocked areas. Alternatively, a healthy blood vessel can be harvested from another part of the body and surgically implanted in the area of a blockage to “bypass” the blockage.
Reversal of atherosclerosis — the Repair Technologies way
Rather than focusing on slowing the progression of atherosclerosis, Repair Technologies is focusing on reversing it. How? By focusing on those troublesome macrophages.
As Reason explains, “Our approach is to provide the macrophages with the ability to break down cholesterol — in particular, oxidized cholesterol and, specifically, 7-ketocholesterol, which is present in older individuals. Normally macrophages ingest lipids and then hand them off to HDL (high-density lipoprotein) particles to be carried back to the liver. But oxidized cholesterols make macrophages inflammatory and unable to perform this task. They become ‘foam cells’ — cells packed with lipids that are no longer passed along and, consequently die, adding their debris to the growing atherosclerotic plaque. In doing so, they call in more macrophages — to their doom.”
Repair Technologies’ goal is to reduce the size of plaques by more than 80%. In pursuit of that goal, Repair Technologies has licensed technology to give macrophages the ability to catabolize cholesterol. Key cholesterol-catabolizing enzymes have been identified in bacteria and humans. Humanized versions of the bacterial enzymes have been expressed in human macrophage cells — and the cells have catabolized cholesterol, including oxidized cholesterol. Not only that, but the macrophages became almost completely immune to the foam cell fate.
Next steps for reversal of atherosclerosis
So, what’s next? Reason says, “We need to more robustly demonstrate catabolism of cholesterol in different macrophage cell lines and primary cell cultures. Then we will conduct cell therapy and gene therapy proof of concept studies in mouse models of atherosclerosis — a process that will run into 2020.” In the atherosclerotic mouse model, monocytes are extracted from mice and engineered to express cholesterol-catabolizing enzymes. The monocytes are expanded in cell culture and then injected back into mice. The mice are observed and compared to control groups.
If all goes well, Repair Biotechnologies may have a product available in the marketplace within the next 4–5 years. But Reason points out that “it would not initially be for atherosclerosis as an indication, as the cost and length of such trials are more onerous than investors are willing to support. Typically, companies in this part of the field instead work to treat forms of familial hypercholesterolemia — in which patients exhibit what is essentially accelerated atherosclerosis. Then deeper pockets launch the necessary trials for atherosclerosis thereafter.”
Repair Biotechnologies vs. the competition for treatment of atherosclerosis
There is a lot of competition in the field. According to Reason, “Far too many to enumerate, but few of them are taking approaches that are likely to work all that much better than statins. Generally, they are lowering cholesterol in the bloodstream or trying to reverse cholesterol transport. The only one I’m aware of that may achieve great success is the newly launched Underdog Pharmaceuticals. They are working on a way to remove 7-ketocholesterol from the body on an ongoing basis, thus preventing macrophages from being driven to dysfunction by this damaging molecule.”
When asked how Repair Biotechnologies stacks up against the competition, Reason answers, “The strategies of lowering blood cholesterol or speeding up reverse cholesterol transport have limited utility, as demonstrated by those than have been trialed or are available in clinics. They only slow the condition somewhat and are incapable of significant reversal of plaque. Our approach should produce significant reversal of the condition, in principle. Further, unlike the Underdog approach, ours can break down many forms of oxidized cholesterol and, since it also breaks down normal cholesterols, it has application to a range of other conditions characterized by excess lipids present in tissues.”
Reason and his quest to repair
And so, at the forefront of anti-aging technology, a man named Reason pursues his quest to repair. Fueled by a desire to live as long as possible, he and Repair Biotechnologies are keeping their sights focused on two key aspects of aging and mortality — thymic involution and atherosclerosis. But, unlike Arya Stark, who became (for a while, anyways) a girl with no name…Reason will remain at the forefront of anti-aging technology as the man with one name.
Karyl Landeau, Ph.D., J.D.
Freelance Writer
To learn more about the Methuselah Foundation, Reason, or Repair Biotechnologies visit: www.mfoundation.org, repairbiotechnologies.com and fightaging.org.
