The stem cell industry took some nasty blows in the early 2000s, when the morality of using embryonic stem cells was questioned and all but a few lines of those cells were excluded from federal research grants. Stem cell experts left the United States for laboratories in Singapore and elsewhere.
In the void that remained, determined stem cell researchers found a way forward: adult stem cells. These cells are found throughout the body—in bone marrow, hair follicles, and other tissues—and they are multipotent, which means they retain the ability to differentiate into some or all of the specialized cell types of the tissue or organ in which they are embedded. Although adult stem cells lack the pluripotency of embryonic stem cells, they can be reprogrammed to become cells of a specific cell type or induced pluripotent stem cells.
The reprogramming technology developed by stem cell researchers is beginning to bear fruit. Although it is not the low-hanging fruit envisaged at the dawn of stem cell science, it is worth the reach. Applications are being developed for basic research, drug testing, and cell-based therapeutics. This last application area, which promises to generate replacement cells and tissues, may be the most important. It is being explored by several companies that hope to manufacture adult stem cells and thereby reinvigorate regenerative medicine. One of companies is Longeveron. By producing allogeneic mesenchymal stem cells (MSCS) from adult human bone marrow MSCs, Longeveron intends to ameliorate diseases and disabilities associated with aging.
Frailty and Diseases of Aging
“I’m a cardiologist, but I’ve long been interested in medical diseases of aging,” begins Joshua M. Hare, M.D., co-founder and CSO, Longeveron. “Heart disease primarily affects older people, and age is a huge risk factor.”
“Frailty associated with aging is an underappreciated problem,” he continues, adding that it affects approximately 12% of all people age 65 or older. Besides becoming familiar with the statistics of aging frailty, Dr. Hare saw it in his practice.
Dr. Hare has been thinking about the causes of frailty among otherwise healthy people for at least 20 years. “Frailty affects so many people of advanced age, yet almost nothing is being done for this group,” he notes. “It represents a huge challenge.”
Aging, he explains, affects all of our organs. “Older hearts don’t work as well as younger hearts, all other things being equal. Therefore, we hypothesized that the decline in function was related to the depletion of normal adult stem cells in the body. Then we found a way to replete them. For us, it was a ‘Eureka!’ moment.”
A Biotech Founded to Bring MSCs to Market
Dr. Hare says that he co-founded Longeveron in 2014 for the express purpose of bringing the benefits of MSC technology to a broad population. “Universities aren’t set up to take a new therapeutic through the regulatory steps to bring a drug to market,” he points out. Rather than hope a biotech company would be interested in acquiring the research, he took matters into his own hands.
Now Longeveron manufactures MSCs in a proprietary process that the company exclusively licensed from the University of Miami. The cells are introduced into the body intravenously.
“The decision to form a company was based on clinical trial results,” he says. He and his team had recently conducted and published the results of a 45-patient allogeneiC human mesenchymal stem cells in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study. Not only were the patients showing positive responses, “they were doing very, very well,” Dr. Hare recalls. “This was exciting because there were no successful medical therapies whatsoever for this condition.” Those trial results were validated by favorable responses from the geriatric medicine community.
One very public sign of approval came in the form of an editorial in the October 2017 issue of The Journals of Gerontology: Series A. The editorial’s authors called MSC translation “a promising and innovative approach for the treatment of frailty in older humans.”
The same issue of the journal also published an article summarizing the results of a small, 30-person study. According to this article, treated patients showed “remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize frailty syndrome.” It concluded that larger trials were warranted.
A Check on Inflammation
The use of MSCs to treat aging “is a new and exciting component of biotech,” Dr. Hare points out. The theory holds that transplanted MSCs can reduce the chronic inflammation associated with aging and aging-related disease, and thereby improve functional capacity and quality of life. At another level, MSCs have the potential to ameliorate diseases and conditions of aging and, perhaps, even increase longevity.
Despite this potential, Dr. Hare cautions against unrealistic expectations: “There are quite a few startups, but few major companies are far along in terms of developing or commercializing this type of therapeutic.”
Slightly more than three years old, Longeveron has one therapeutic in Phase IIb clinical trials. Additional trials are open. Some are focused on aging frailty; others are evaluating the cells as a way to treat Alzheimer’s disease.
The Competitive Landscape
Designed from MSCs extracted from bone marrow, the therapeutic product is allogenic. It can be made in large quantities and will be available off-the-shelf. Currently, says Dr. Hare, there are no MSCs on the United States market, although one MSC therapy has been approved. Also, two or three companies are pressing ahead with the development of MSC therapies.
According to Dr. Hare, Longeveron’s MSCs are unique in two respects: the way they are produced, and the way they are characterized. The specifics of manufacturing and the cells’ characterization features, however, are confidential. “They are trade secrets,” Dr. Hare insists.
In a recent interview, Dr. Hare was not only reticent about Longeveron’s technology, he was also vague about the specific challenges the company has weathered—but not because all these challenges are particulalry sensitive. He was hurrying to help a patient. He did mention, however, challenges pertaining to the specific (and confidential) methods used to turn a cell into a drug, and the FDA guidances for those methods. The next step for the young company, he said, is to begin negotiations with the FDA to design Phase III trials.
In January, Longeveron won a research grant from the National Institutes of Health (NIH) to develop therapeutics to combat metabolic syndrome. The $1.15 million grant is part of the NIH Fast Track program for small businesses. Earlier, the company received clinical trials funding from Alzheimer’s Association and Maryland’s Technology Development Corporation (TEDCO).
Dr. Hare attributes Longeveron’s success to date to a capable team. Dr. Hare himself is founding director of the University of Miami’s Interdisciplinary Stem Cell Institute (ISCI). The scientific advisory board includes thought leaders in geriatrics and cardiology from leading institutions in the United States and Japan. Management team members have histories in academia and corporate operations. None, however, has taken a drug to market.
In the end, a lack of commercialization experience may not matter. Longeveron, recognizing its strengths, plans to partner for that phase of its journey.
A Booming Market
If future trials are as successful as Dr. Hare hopes, Longeveron’s new therapy will be firmly on the path to commercialization. Given the global population of aging baby boomers, he envisions a broad market for the therapy.
“People came to us in droves for the clinical trials,” Dr. Hare reports. “Having the signs and symptoms of frailty troubles people. They have a palpable sense of becoming disabled simply because they are aging. They want to improve their quality of life.”
Regenerative therapies already are gaining regulatory approval for many indications. And, while aging has been largely ignored, it is unlikely to be ignored much longer.
If Longeveron’s approach is eventually commercialized, in the not-too-distant future, any geriatrician or general practice physician should be able to administer Longeveron’s MSCs to roll back frailty and possibly reduce other deficits in functional capacity related to aging, such as Alzheimer’s disease and metabolic syndrome.