A Great Deal More Funding for the Development of Partial Reprogramming Therapies
The medical biotechnology and pharmaceutical investment market was always very risk averse, giving rise to the valley of death between preclinical seed funding and early clinical stage funding; there are all too few investors willing to fund companies to move from late preclinical stage to early clinical stage. They would rather let promising companies die out and pick from the few that somehow find funds to run a first clinical trial in human patients than take the risk on a preclinical program. Further, investment is a herd industry, it polarizes to a few hot areas, fads, and sure things. In the recent years of various flavors of poor market environment for biotechnology and pharmaceutical drug development it seems that these tendencies have grown more exaggerated. A sizable fraction of all biotech investment pours into a small number of cellular reprogramming initiatives, a hot area of research and development, while investors have largely retreated from preclinical funding more generally. It will be interesting to see how long this lasts, as it is clearly unsustainable for every initiative in the field other than reprogramming.
This year alone has seen sizable funding devoted to Retro Bio and NewLimit for reprogramming efforts, though in fairness Retro Bio does have a number of other programs on the go. Life Biosciences raised a relatively smaller but still sizable amount in the grand scheme of things for their clinical trials in reprogramming. Couple all of this to the even greater funding still possessed by Altos Labs, and it seems fair to say that partial epigenetic reprogramming is the one area of aging-related biotechnology that needs no further assistance from patient advocates and other folk. Over the next decade or so we should expect the development community to establish answers to all of the fundamental questions regarding the construction of viable therapies based on reprogramming.
It remains strange to me that partial reprogramming captured the market and the interest in this way rather than senolytic therapies to clear senescent cells, given that senolytics were first on the scene by some years, and senolytic research continues to boast a far larger and more impressive portfolio of animal data for reversal of age-related disease and dysfunction. There is no accounting for how things turn out sometimes. Once enough funding flocks to a cause, there is a tipping point, and its popularity becomes a self-fulfilling prophecy. The funding carves a channel for more funding.
No limits: NewLimit lands $435m ahead of human trials
NewLimit believes it has found a way to help older liver cells behave more like younger ones. That idea sits within a growing area of longevity science known as epigenetic reprogramming. The company has raised $435 million in a Series C financing round led by Founders Fund, with participation from Thrive Capital, Greenoaks, Quiet Capital and existing investors including Kleiner Perkins, Eli Lilly Ventures and Human Capital. More notably, the company says it plans to bring its first age-reprogramming medicine into human clinical trials next year - a milestone it once thought was more than a decade away. Just a year ago, NewLimit closed a $130 million funding round and was still talking about the long road toward a clinic-ready therapy. Then something changed. According to NewLimit, a promising candidate emerged from the company's research platform far sooner than expected, prompting the company to accelerate its plans.
Today, we're announcing the initial close of our next financing round at a pre-money valuation of $1.8 billion, led by 4P Capital alongside a group of investors who believe Retro is uniquely positioned to translate the biology of aging into a new generation of medicines. In three years, Retro moved from its first lab to a clinical candidate. In 15 months, that candidate RTR242 went from indication selection to first-in-human dosing. Alongside that progress, we've built cell therapy, tissue reprogramming, and AI-enabled protein engineering programs, all designed to support a growing pipeline of therapeutics targeting the underlying drivers of aging and age-related disease.
I think this area of longevity got hot for investors because of one lead investor, Jeff Bezos, who pumped a lot of money into Altos Labs. And I suspect Mr Bezos did this because he is familiar with DNA and the concept of genetic engineering and Yamanaka factors making induced pluripotent stem cells has been a popular science media topic since the early 2000s, whereas senescent cells are still a far more obscure topic.
A lot of the small molecule senolytics like Dasatinib and Navitoclax are cancer drugs with fairly nasty side effects at the doses used to treat cancer which I think leads to some caution amongst self experimenters. They are also off patent which might lead to caution amongst a clued up early stage investor. I think some kind of cell penetraing peptide such as Helicons (chemically stabilised Alpha Helical peptides) or Spiroligomers (chemically stabilized ladder peptides) could be developed as a topical skin treatment , then as a whole body senolytic without side effects.
The Conboys did a sort of reprogramming with TGF beta suppression and oxytocin and noted reduced senescent cell burden.
Senolytics are interesting but if you go upstream to the right place you solve more problems simultaneously. It's too hard to micromanage all the downstream points of failure.
"We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. The dose of Alk5 inhibitor (Alk5i) was reduced by 10-fold and the duration of treatment was shortened (to minimize overt skewing of cell-signaling pathways), yet the positive outcomes were broadened, as compared with our previous studies. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice.
Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo.
Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging."
https://pubmed.ncbi.nlm.nih.gov/31422380/