“Niche player” can be a dubious distinction. The term is usually used to express admiration for the mastery of a specialty, but it can also be used to suggest that the specialty is limiting. Fortunately for stem cell companies, “niche” has mostly positive connotations. A niche, for stem cells, is an environment that promotes self-renewal and differentiation. Similar dynamics are at play in the stem cell field. There are emerging technologies, new applications, and expansion opportunities. Specialties, then, needn’t represent dead ends. Instead, they can serve as points of departure.
The stem cell companies described in this article are all full of potential. Some are developing therapeutics for challenging diseases such as cancer, diabetes, and Alzheimer’s. Some are refining technologies to improve stem cell self-renewal and differentiation, including technologies to support the creation of better three-dimensional organ models. Finally, some are offering biomanufacturing platforms and services.
For these companies, the possibilities seem endless. Even more numerous are the possibilities for individual companies to form value chains that together form a growing, thriving market, much like individual stem cells give rise, ultimately, to a fully realized body.
The advantages of medicinal signaling cells
The scientist who coined the term “mesenchymal stem cell” has been having second thoughts. That scientist is stem cell pioneer Arnold J. Caplan, PhD, professor of biology and director of the Skeletal Research Center at Case Western Reserve University. He suggests that a better term would be “medicinal signaling cell.” Either way, the popular “MSC” acronym would remain.
According to Caplan, the advantage of the new term is that it deemphasizes the in vitro multipotential capacities of MSCs, which have been receiving little attention in clinical trials, and instead emphasizes how MSCs can home in on sites of injury or disease and secrete immunomodulatory and regenerative factors.
The updated take on MSCs must be appreciated by Longeveron, a company that develops cell-based therapies for aging-related medical conditions, such as frailty, that affect a considerable percentage of the general population and leads to low quality of life, dependency, medical complications, and mortality. “Our mission is to bring the proprietary medicinal signaling cell formulation that we developed to the market,” says Anthony Oliva, PhD, senior scientist, Longeveron.
Lomecel-B, Longeveron’s lead investigational therapeutic candidate, is derived from culture-expanded MSCs obtained from the bone marrow of young, healthy adult donors. In a recently completed multicenter, randomized, double-blinded, placebo-controlled Phase IIb clinical trial, a single intravenous infusion of Lomecel-B led to a statistically significant improvement nine months later in older adults with physical frailty.
“We found a dose-dependent improvement in the six-minute walk test.” Oliva details. “Participants in the highest dose arm showed an increase from baseline of nearly 50 m on the six-minute walk test distance, and over 60 m versus placebo. These results exceed previously reported minimal clinically important differences in frail patients.” The six-minute walk test is a commonly used measure of mobility and endurance for a variety of diseases and conditions, including certain heart-related diseases, Duchenne muscular dystrophy, and aging-related frailty.
A potential advantage of Lomecel-B that Longeveron has been exploring in its clinical trials is the possibility of administering the donor cells without triggering a harmful immune rejection in the recipient. “Unlike organ transplants, such as heart or liver transplants, MSCs do not have to be tissue-type matched,” Oliva points out. “That opens the possibility of using cells derived from a single donor as an off-the-shelf treatment for large numbers of patients.”
Longeveron developed protocols to freeze and store well-characterized MSCs that have been cultured and expanded. The company aims to produce Lomecel-B on a large enough scale to ensure that demand for the therapeutic can be met if FDA authorization is received. “We hope to make cost-effective treatments available more broadly,” adds Dan Gincel, PhD, senior vice president at Longeveron. “Every drug development process is expensive, but while small molecules cost cents to dollars to make once the process has been worked out, making cell-based therapies is still very expensive relative to small-molecule drugs.”
MSCs have many potential applications because they have multiple mechanisms of action. MSCs release growth factors, anti-inflammatory cytokines, and exosomes. “They can also participate in cell-cell interactions with host stem cells and initiate regenerative or repair responses,” Oliva remarks. In addition, MSCs can form nanotube bridges with other cells and exchange mitochondria and other organelles. With all these mechanisms, MSCs can offer multiple benefits. They fall in two main groups: pro-vascular effects and anti-inflammatory activities.
Lomecel-B’s multiple mechanisms of action could address multiple features of Alzheimer’s disease. Consequently, Longeveron is testing Lomacel-B as an Alzheimer’s therapeutic. This work complements the company’s studies of Lomacel-B as a way to counter physical frailty, given that Alzheimer’s can be considered the cognitive correlate to physical frailty.
“When we have a preventative medication or a cure, [it will likely be] a combinatorial therapy,” suggests Oliva. He adds that one of its essential components will likely be a cell therapy, such as Lomecel-B.
The few approved drugs for Alzheimer’s disease are symptomatic treatments, with the exception of the recently approved aducanumab, which selectively targets beta-amyloid but has limited efficacy. Like aducanumab, many investigational drugs currently under evaluation address a single aspect of Alzheimer’s disease pathology. Hence, these drugs, too, may have limited efficacy.
“It is critical to address the fundamental inability of the central nervous system to repair itself,” Oliva declares. “This is where using a regenerative medicine approach, such as one incorporating Lomecel-B, will be essential to stimulate the intrinsic regenerative responses that the brain does not initiate on its own.”
Nicotinamide to maintain stemness
“For some patients, finding a donor is easy, but for others, a donor is not always available,” says Ronit Simantov, MD, chief medical officer at Gamida Cell. “This is particularly true in patients who are ethnic or racial minorities or of mixed ethnic heritage.”
Much of Gamida Cell’s work involves developing cell-based therapies for patients with solid tumors and hematopoietic malignancies. One of these therapies is omidubicel, an investigational cell-based therapy for allogeneic hematopoietic stem cell transplantation. Omidubicel, which is derived from appropriately HLA-matched umbilical cord blood and comprised of ex vivo–expanded hematopoietic progenitor cells, is the first bone marrow transplant product to receive breakthrough therapy designation from the U.S. Food and Drug Administration.
Omidubicel may prove to be an attractive alternative to standard umbilical cord blood transplant in patients with high-risk blood cancers who do not have a suitable matched donor. Umbilical cord blood has been an important source of pluripotent stem cells. In addition, it presents the advantage of being immunologically naïve. However, it may provide too few stem cells to populate an adult patient.
“What omidubicel sought to do,” Simantov points out, “is expand the stem cells in cord blood while maintaining their stemness.” Stemness is critical in pluripotent stem cells. It allows them to divide, differentiate, and repopulate the hematopoietic system. But according to many studies, stemness may fade during stem cell expansion. Stem cells may differentiate or lose their ability to renew too early.
“Using nicotinamide, we found a way to culture the stem cells and expand them while preserving their functionality and their phenotype,” Simantov reports. This approach works because nicotinamide can reduce the sensitivity of the stem cells to free oxygen radicals. Essentially, nicotinamide-containing culture mimics the hypoxic bone marrow environment.
Omidubicel has been tested in a Phase III randomized global clinical trial. The therapy met its primary endpoint (a statistically significant reduction in time to neutrophil engraftment) and all its secondary endpoints. The results are being submitted for regulatory review.
“Developing omidubicel helped us understand the challenges of expanding hematopoietic stem cells in culture as well as the logistics of delivering them to patients,” Simantov notes. “This experience can be extended to other cell types—and other diseases.” An additional asset in Gamida Cell’s pipeline is GDA-201, a nicotinamide-enhanced natural killer cell that was tested in patients with lymphoma. “We are in the process of opening a clinical study that uses GDA-201 in patients with non-Hodgkin lymphoma,” Simantov notes. “We also have a pipeline of natural killer cells genetically enhanced in different ways to allow them to specifically target other tumors such as multiple myeloma and several solid tumors.”
Spheroid technologies to more accurately study signaling
“Our spheroid technology is different from other existing technologies,” declares Brian Pollok, PhD, scientific advisor, board member, and co-founder of Propagenix, a company that develops cell bioproduction platforms for biopharmaceutical companies working on regenerative medicine applications involving epithelial barrier tissues. “We do not rely on any kind of Wnt or Lgr5 receptor agonist,” he adds. “Instead, we use a pharmacological approach to stimulate the basal stem cells.”
Propagenix’s EpiX solution, a cell-free and serum-free cell culture medium, can expand human epithelial stem and progenitor cells from various tissues and organs, including the skin, the airways, the kidney, the corneal epithelium, and the mammary and prostate glands. In a sense, EpiX can help in vitro stem cells behave more like in vivo stem cells, which have lifetime renewal capabilities. Such capabilities are hard to sustain in conventional media, which impose various stresses on in vitro stem cells, limiting their ability to expand.
EpiX relies on a knowledge-based collection of small molecules and recombinant human proteins that modulate diverse biological pathways critical for stem cell self-renewal and differentiation. As compared to conventional media, which supports a 10,000-fold expansion of epithelial stem cells, EpiX allows their expansion by over one trillion-fold.
Scientists at Propagenix developed research-scale methods to create apical side–outward airway spheroids. “The orientation of our spheroids is unlike that of typical organoids,” Pollak explains. “We control the substrate matrices so that the apical surface of the cells is facing outward, exposed to the environment.” In spheroids that have this orientation, environmental factors, such as infectious agents, drugs, and toxins, will establish the first contact with the apical surface of the cells and more accurately recapitulate the natural process of pathogenesis.
Creating better stem cells for bioproduction
“People still use the same cell lines that were developed 50 years ago,” observes Alan Moy, MD, founder and CEO of Cellular Engineering Technologies (CET). “Our company is interested in creating new cell lines that offer advantages over the current ones for bioproduction.”
CET specializes in cell manufacturing and contract research services directed toward biopharmaceutical market segments that interface with stem cell technology. The company is researching various technologies to expand existing applications for stem cells beyond the traditional regenerative medicine landscape. “When CRISPR is used,” Moy details, “human somatic stem cells can be genetically modified to generate cells that are more specific, more defined, and better in efficacy and safety.”
In regenerative medicine, pluripotent stem cells have attracted considerable interest for their potential in cell and tissue replacement applications. For example, preclinical studies have successfully used pluripotent stem cells to replace damaged cells, such as the damaged dopaminergic neurons that underlie Parkinson’s disease or the damaged pancreatic beta cells in type 1 diabetes.
“One of the problems with induced pluripotent stem cells is increased neoplastic risk,” Moy explains. The high potential of tumorigenesis has been one of the biggest obstacles in their clinical use, a risk that is explained by their ability to acquire genetic and epigenetic changes that can lead to malignant transformation. “Starting with induced pluripotent stem cells that have a greater safety profile is very important,” Moy insists.
In a recent study, Moy and colleagues described, for the first time, a technology to reprogram adherent cells into virus-free and oncogene-free induced pluripotent stem cells with superior safety profiles. CET was granted a patent from the U.S. Patent and Trademark Office for this technology.
A challenge when using induced pluripotent stem cells is that many therapeutic differentiation processes depend on growth factors that are derived from bacteria, which lack post-translational modifications that are present in human cells. “This is where our company has come full circle with the bioproduction of human somatic stem cells,” Moy remarks. “These cells create growth factors and proteins that have fully native post-translational modification.”
Encapsulated stem cells to cure diabetes
As a regenerative medicine company, ViaCyte focuses on developing and delivering cell replacement therapies to treat human diseases. For example, ViaCyte is advancing stem cell–derived islet cell replacement therapies to treat insulin-requiring diabetes, including type 1 and type 2. Clinical trials are being conducted at several sites in the United States, Canada, and Europe.
“ViaCyte has become the first company to implant differentiated stem cells in patients living with diabetes,” declares Timothy Kieffer, PhD, the CSO of ViaCyte and a professor of cellular and physiological sciences and surgery at the University of British Columbia. “We have performed cell implants in more than 100 individuals.”
In patients with type 1 diabetes, current insulin replacement involves daily dosing, by needle injection or pump, and the careful monitoring of blood glucose levels. Too little insulin causes elevated blood sugar levels that, over time, can lead to debilitating complications such as retinopathy, neuropathy, and nephropathy, while too much insulin may cause dangerous and even life-threatening hypoglycemia. Therefore, insulin must be delivered at the right time, and in the correct quantity, to ensure the tight control of blood glucose levels.
“ViaCyte has developed a process to manufacture pancreatic islet cells from human pluripotent stem cells at large scale, which can be implanted into insulin-requiring patients,” Kieffer explains. In clinical trials, ViaCyte scientists demonstrated that these cells resemble the natural insulin-producing cells from the endocrine pancreas and are capable of producing insulin in a meal-dependent manner, reducing a patient’s reliance on exogenous insulin administration.
“ViaCyte is the only company to have achieved this with macro-encapsulation devices designed for subcutaneous implantation,” Kieffer adds. “We are working with scientists at Gore [W. L. Gore & Associates] to develop new membranes that will enable the devices to fully isolate the differentiated stem cells from the host’s immune system.”
Over two decades ago, researchers at the University of Alberta demonstrated that it is possible to effectively treat diabetes in patients by infusion of a few teaspoons of islet cells isolated from multiple donors. This approach became known as the so-called “Edmonton Protocol.” The cells, which are purified from the donor pancreas and infused into the recipient’s portal vein, provide an endogenous supply of insulin. However, a major limitation of this strategy is the need for prolonged immunosuppression to prevent immune rejection of the donor cells. According to Kieffer, the need to identify an unlimited cell source and the need to avoid chronic immunosuppression (to protect the cells from both alloimmunity and autoimmunity) “have remained barriers to the widespread implementation of this approach.”
ViaCyte hopes to overcome these barriers by partnering with CRISPR Therapeutics on the development of a cell replacement therapy for type 1 diabetes. The therapy, which is called VCTX210, is an investigational, allogeneic, gene-edited, stem cell–derived product. In February 2022, the companies announced that the first patient in a Phase I trial had been dosed with VCTX210. According to a clinical investigator in the trial, the dosing represented a “historic, first-in-human transplant of gene-edited, stem cell–derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression.”
“We hope,” Kieffer relates, that the stem cell–derived product “will achieve the holy grail of regenerative medicine, an off-the-shelf cell line that could be used for patients with insulin-dependent diabetes without the need for chronic immunosuppression.”