Is the Promise of Stem Cells Finally Being Realized?

From the minute an organism is born its cells and tissues are subject to an array of insults and injuries, some small and some major. While we have made progress on numerous fronts to prevent, treat, or slow many diseases, the holy grail remains regenerative therapies designed to replenish and repair tissue or organs impaired by disease, trauma, or congenital defects.

Even though the field of regenerative medicine is quite broad, cellular therapies, commonly referred to as stem cells, have received the lion’s share of attention. That’s because under the right conditions stem cells can differentiate into any cell type and/or many cell types. Regenerative medicine utilizing stem cells offers greater likelihood of success in reversing chronic diseases when compared to conventional therapies. Stem cells could be viable alternatives and cost-effective solutions for chronic conditions, including macular degeneration, soft tissue and orthopedic conditions, cardiopulmonary disease, cancer, neurodegenerative disorders, and metabolic disorders.

Traditionally, stem cells have been characterized by their source. For example, embryonic stem cells are collected from early embryonic tissues, while adult stem cells are harvested from a number of different tissues, including bone marrow, fat, and reproductive organs. Today, however, these terms are insufficient as scientists have discovered how to turn fully differentiated adult cells back into embryonic-like cells, creating induced pluripotent stem cells (iPSCs). Conversely, adult stem cells, more correctly termed “somatic” stem cells, meaning “from the body”, have been found in the fetus, placenta, umbilical cord blood and infants.

Therefore, the current preference is to categorize stem cells based on their differentiation potential, and for clinical purposes these are either pluripotent or multipotent stem cells. Pluripotent stem cells are so named because they can differentiate into all cell types in the body. Originally identified in embryos, pluripotent stem cells are only present for a very short period during embryonic development before differentiating into the more specialized multipotent stem cells that eventually give rise to the specialized tissues of the body. Multipotent stem cells differentiate into cells of a particular germ line (endoderm, mesoderm, ectoderm) or cells of a particular tissue.

The use of pluripotent stem cells is appealing because of their limitless differentiation; however, they have some drawbacks as well. For example, the use of human embryonic stem cells is controversial because the embryo is destroyed by the isolation process. In addition, embryonic stem cells exhibit neoplastic propensities and display genetic instability. While iPSCs do not elicit the same ethical concerns, they still have significant challenges with respect to safety, potency, genetic stability, immunogenicity, tumorgenicity, cell reproducibility, and scalability.

Multipotent stem cells offer many of the same advantages as pluripotent stem cells without many of the inherent risks. Mesenchymal stem cells (MSCs) are a type of multipotent stem cell that can be isolated from various adult or fetal tissues. Once isolated, they readily proliferate in culture and depending on their surrounding environment and the presence of specific growth and differentiating factors, they can be stimulated to differentiate into numerous mesodermal cell types, including adipocytes, osteocytes, and chondrocytes. There is some evidence that they can also differentiate into cells derived from other embryonic germ layers, such as neurons derived from the ectoderm, and hepatocytes derived from endoderm. Due to their plasticity, as well as their ease of isolation and propagation, the MSCs are considered the most important cell type for regenerative medicine and are the most widely studied in preclinical and clinical trials.

Clinical trials using MSCs in companion animals with naturally occurring diseases have provided some of the most important information on their safety and efficacy, which has benefited both humans and animals. For example, osteoarthritis is common in dogs, cats and horses, and a number of studies have demonstrated that MSCs may be beneficial in the treatment of this condition. Several studies in dogs with partial or complete cranial cruciate tears demonstrated that MSCs, administered either alone or in combination with platelet-rich-plasma (PRP), decreased the severity of clinical signs and the inflammatory response. While the results were promising, they were pilot studies with small sample numbers. However, a prospective, double-blinded, placebo-controlled clinical trial in dogs with chronic elbow osteoarthritis demonstrated significantly improved pain and lameness scores in dogs treated with MSCs as compared to dogs given a placebo. Similarly, a review of numerous studies conducted in horses found that MSCs were efficacious in the treatment of osteoarthritis, as well as tendon and ligament injuries.

While we have other treatments for osteoarthritis, MSCs show promise in treating some conditions for which we currently have no effective therapy. For example, some cats suffer from Feline Chronic Gingivostomatitis (FCGS), a chronic, inflammatory condition of the soft tissues of the mouth. It is extremely painful, and many cats suffering from FCGS are euthanized for humane reasons. Fortunately, the results of several recent studies demonstrated that MSC treatment significantly decreased the severity of mouth lesions and improved clinical signs.

Based on the positive results found in earlier studies, one of our portfolio companies, Gallant Therapeutics, is currently conducting a large clinical trial assessing the efficacy and safety of MSCs for the treatment of FCGS. Initial results have been extremely promising, and if successful, Gallant will have the first MSC product approved by the FDA for use in any animal. Equally important, we will have a new therapeutic modality to treat cats suffering from this painful and debilitating condition.

Gallant is developing a pipeline of cellular therapies for use in canine and feline diseases. This pipeline is enabled by Gallant’s manufacturing process that isolates and grows MSCs from uterine tissue, which is normally discarded when female dogs and cats are neutered. The health histories of the donor animals are reviewed and approved by the FDA to ensure that the isolated cells are of the highest quality. These MSCs are referred to as allogeneic stem calls, because they are collected from one animal, but administered to a different animal of the same species. The use of allogenic cells, as opposed to autologous, which are collected from and administered to the same animal, is critical to the manufacturing process, allowing it to be conducted under Good Manufacturing Practices (GMP) in a facility that is inspected and approved by the FDA.

While many conditions may be responsive to MSC therapy, including atopic dermatitis, asthma, and inflammatory bowel disease, some conditions and diseases appear refractory. For example, while the results of one small, but randomized and placebo-controlled study failed to find any clinically significant improvement in cats with naturally occurring chronic renal failure, a different, open-label baseline-controlled safety study found that MSCs improved some renal parameters, such as serum creatinine and urine specific gravity. More research is needed to understand why some conditions respond well to MSC therapy while others do not.

Another question about the therapeutic effects of MSCs is their mechanism of action. In most cases the cells do not migrate to and differentiate into the tissue-specific cell types as originally thought. Rather, it has been proposed that they act by secreting numerous bioactive substances including cytokines, chemokines, and growth factors, as well as exosomes and vesicles, that stimulate tissue repair and recruit MSCs already present in the tissue. Together, this secretory milieu has been termed the secretome and there have been efforts to harvest it from cultured MSCs for use in diseases responsive to MSC treatment.

While stem cells may never deliver the holy grail of truly regenerative medicine, it is clear we are starting to unravel some of their mysteries. It is also fitting that animals, which have provided us with many of the insights on how and where these therapies may be most effective, may be some of the first to benefit from their development. We look forward to seeing where Gallant Therapeutics and other companies like them take this new therapeutic modality and we are excited to be along for this promising journey.

– Cindy Cole, DVM, PhD, DACVCP






First Five
First Five is our curated list of articles, studies, and publications for the month

Loving the grey
Turning grey in humans is usually associated with aging and rarely met with delight. Horses also turn grey with age, but it happens when horses are young, and many humans celebrate it. Grey horses are generally born dark bay or black and within the first year or two of life their coat turns dark dappled grey, a color popular with many horse owners. Eventually their coat loses most of the melanin and by their teens grey horses are fully white with only speckles of grey. Unfortunately, grey horses also develop melanomas at a significantly higher rate than horses of any other color. A recent study demonstrated that a specific type of mutation, termed a copy number variation (CNV) associated with the gene Syntaxin 17 is the causal mutation for both greying and the development of melanomas in the horse. In a genetic screen comprising more than 700 Grey horses representing eight different breeds, the presence of this CNV was shared by all horses, providing evidence that all grey horses world-wide trace back to a single common ancestor in which the mutation arose. How mutations in the Syntaxin 17 gene drive the development of greying in horses and melanomas is not understood, but it is the subject of continued research. It is hoped that a better understanding of the relationships may lead to better diagnostics and improved treatments for these tumors in horses and perhaps other mammals including man.

In the Eye of the Beholder
Most mammalian species have only one eye color, but like humans, cats, both wild and domestic exhibit a broad array of eye colors. The origins of this unique trait were determined in a recent study that used machine learning analysis of public photographs. Five felid eye colors were identified: brown, green, yellow, gray, and blue and then using a phylogenetic tree, the researchers set out to reconstruct the ancestral state. They determined that the early pre-felid lineages had only brown eyes, then grey-eyed felines appeared, likely due to a genetic mutation that drastically decreased the amount of pigment in the eye. This mutation allowed the expression of other colors that would typically be overshadowed by the dominant brown. These findings enhance the understanding of eye color evolution, and the methods used can be applied to phylogenetic reconstruction of color beyond irises.

Dog talk?
Most dog owners talk differently to their dogs than their human friends and families and a recent study proposes a reason why. Using acoustic analyses of dog vocalizations, researchers determined that their main production rhythm is much slower than the average human speech rate. The study also identified that humans typically speak to their dogs at a slower rate than they speak to other humans.  Researchers hypothesize that humans may unconsciously adjust their speech rate, as we do with babies and children, to this shared temporal channel as a means to improve communication.

It's not the age, it’s the mileage
A recent study from the UK Biobank project used plasma proteomic signatures to define “youthful” versus “aged” status of 11 organs. The study results support the hypothesis that organs age at different rates and that the development of organ-specific disease can be predicted based on the biological age of the organ. For example, an individual with a proteomic signature consistent with an aged heart was at higher risk of cardiovascular disease than an individual with a youthful signature, regardless of their actual age. In addition, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity.

It’s not just bees
The Ethiopian wolf (Canis simensis) is the rarest wild canid species in the world and Africa’s most threatened carnivore. Endemic to the Ethiopian Highlands, fewer than 500 individuals survive. Recently, University of Oxford researchers observed the wolves lapping up the nectar of Ethiopian red hot poker (Kniphofia foliosa) flowers. This is the first large carnivore species ever to be recorded regularly feeding on nectar. Some of the wolves were seen visiting as many as 30 blooms in a single trip. As they lick the nectar, the wolves’ muzzles get covered in pollen, which could potentially be transferred from flower to flower as they feed. The researchers found the behavior interesting because it shows nectar-feeding and pollination by non-flying mammals might be more widespread than currently recognized and demonstrates that the ecological significance of these lesser-known pollinators might be more important than currently appreciated.

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