Mesenchymal Stem Cell Transplants Trialed as a Therapy for Age-Related Frailty

At least one group is running trials of stem cell transplants as a potential treatment for age-related frailty syndrome: the scope of the possible in the near term is to find way to incrementally improve the condition, not produce a sizable reversal, but that is an improvement over the current situation, given that there is no effective treatment. The closest thing to a standardized, proven, reliable class of stem cell therapies involves the use of mesenchymal stem cells, sourced from a patient, or from lines of cells grown and engineered for transplantation with minimal risk. The primary outcome of mesenchymal stem cell therapies, or at least the reliable outcome, is a reduction in the systemic, chronic inflammation that accompanies old age. While it is entirely possible that other mechanisms are at work, the cells typically don't last long following transplantation, and thus it is the brief signaling changes that must produce benefits that can last for months or longer.

Chronic inflammation is a major problem in aging. It drives progression of most of the age-related conditions, and high levels of inflammation are certainly considered to be a major component of frailty syndrome in the old. In the context of a general treatment for frailty based on reductions in inflammation, the focus is less on the acceleration of specific age-related conditions over time, however, and more on the immediate consequences of constant high levels of inflammation for cell biochemistry, pain, cognitive function, joint function, regeneration, and tissue maintenance. Many aspects of age-related dysfunction are to some degree being actively maintained in their current impacted state by the presence of inflammation - take away that inflammation, and the problems subside a little, back to the lower level of harm and loss expected due to accumulated cell and tissue damage.

In recent years, it has become clear that chronic inflammation, as opposed to the normal short-term inflammation resulting from injury or infection, disrupts the finely tuned dance carried out between tissue and immune system needed for regeneration. This is an emerging theme in the investigation of how senescent cells cause aging, for example, as these unwanted cells are potent sources of inflammatory signaling. So if we see unreliable or marginal benefits from stem cell therapies that look like enhanced regeneration, it might well be that this is at root a short-term reduction in the age-related disruption of tissue maintenance - perhaps enough to allow a little reconstruction to take place in some patients. This is speculation, of course, and the cellular biochemistry is challenging to investigate; we should probably expect a first generation of moderately reliable therapies in advance of complete understanding of their mechanisms. Here is another point to consider on this topic: if the inflammation model of benefits is correct, then clearance of senescent cells should be at least as good a treatment for frailty as mesenchymal stem cell transplant, and probably better and more lasting.

Stem Cell Transplantation for Frailty

It was reported over 50 years ago that old age is associated with depletion and loss of function of stem cells. Since that time, there has been extensive research confirming the deleterious effects of aging on all types of stem cells, and a growing belief that such age-related changes in stem cells further accelerate tissue and organismal aging. There have also been hundreds of early-phase clinical trials using mesenchymal stem cells (MSCs) for a wide range of disorders including graft-versus-host disease, autoimmune disease, and heart disease where both regenerative and immunomodulatory effects of MSC are harnessed.

The possibility that stem cells might be "vehicles for youthful regeneration of aged tissues" has been well recognized. Mesenchymal stem cells from young mice infused into old mice improved age-related osteoporosis and also increased life span. Transplantation of stem cells from young mice to old mice has also been reported to improve cardiac and reproductive function. There is clearly an opportunity to now undertake clinical trials to explore the therapeutic potential for stem cell transplants for age-related conditions in older humans.

Frailty provides an ideal target for clinical trials of MSC transplantation and aging. Frailty in older humans is associated with reduced circulating MSC, while many of the clinical features of frailty involve mesenchymal tissues, that is, the musculoskeletal system. In clinical practice, the diagnosis is often made based on clinical impression rather than any formal diagnostic process. The definitions of frailty overlap with definitions of aging and sarcopenia. Frailty can be considered to be the end-stage consequence of the biological processes of aging and accumulated chronic disease. Recently two clinical trials were published on the effects of MSC transplantation in frail older humans, and these trials represent potential landmarks in the treatment of frailty. Both studies are early-phase trials of a small number of participants, designed primarily to assess safety, so conclusions about efficacy need to be treated with caution. Even so, the results are striking and, at minimum, pave the way for large randomized Phase III clinical trials.

The first study was a Phase I open-label trial where allogeneic MSC collected from the bone marrow of younger donors aged 20-45 years were used to treat 15 frail patients (average age 78 years) using a single infusion of either 50, 100, or 200 million cells. After 6 months, outcomes that improved included the 6-minute walk and tumor necrosis factor α (TNFα) levels, with variable improvements in forced expiratory volume in 1 second (FEV1), Mini-Mental State Examination (MMSE), and quality of life. No significant adverse effects were recorded, and only one patient developed antibodies that could potentially neutralize the outcomes.

The second study by the same group was a Phase II randomized, double-blinded trial of allogeneic MSC at two doses (100 or 200 million cells) versus placebo. The participants were 30 frail patients with an average age of 76 years. No therapy-related adverse effects were documented at 1 month. Improvements were reported for physical performance, the 6-minute walk test, short physical performance exam, FEV1, and TNFα mostly in the 100 million cell groups. The authors conclude that the treated groups had "remarkable improvements" in outcomes. There are always caveats associated with interpreting efficacy in small numbers of subjects, yet it is remarkable that a single treatment seems to have generated improvement in key features of frailty that are sustained for many months.

Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty

The purpose of this Phase 1 pilot study, AllogeneiC Human Mesenchymal Stem Cell in Patients with Aging FRailTy via IntravenoUS Delivery (CRATUS), was to evaluate the safety and tolerability of allogeneic hMSCs (allo-hMSCs) in patients with aging frailty and to explore domains of treatment efficacy of allo-hMSCs through the reduction of signs and symptoms of aging frailty. The major new findings of CRATUS are that intravenous allo-hMSC infusions are safe and well tolerated in elderly individuals with early signs and symptoms of frailty. Importantly, there were improvements in a constellation of parameters that are important predictors of morbidity and mortality in patients with aging frailty.

With no current standard of care for frailty, allo-hMSCs may hold great promise as a cell therapy agent for patients with this syndrome. The underlying basis for positive effects of allo-MSCs are likely due, at least in part, to anti-inflammatory and proregenerative effects. In this regard, frailty is characterized by systemic inflammation and low "reserve capacity" of organ systems thought due to diminished endogenous stem cell production. Replenishment of the body's stem cell "factory" and/or revitalization of stem cell niches via intravenous infusion of allo-hMSCs may help treat the morbidities associated with aging frailty.

Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial

There are no specific medical or biologic treatments that ameliorate or reverse frailty. Stem cell depletion is a key mechanism postulated to contribute to frailty. In this regard, we recently conducted a phase I open label study of human allogeneic mesenchymal stem cells (allo-hMSCs) intravenously infused for frailty, which showed that the cells could be safely administered, improved measures of functional capacity, and reduced inflammation. Therefore, we conducted the current phase II double-blinded and placebo-controlled study in order to test the hypothesis that exogenous allo-hMSCs could reverse signs and symptoms of frailty in older individuals.

Similar approaches have been shown to exert beneficial effects on the cardiovascular system, with functional improvements on various types of heart disease, endothelial function, and systemic inflammation. Given their pleiotropic mechanisms of action, which include antifibrotic, anti-inflammatory, proangiogenic properties, and their ability to stimulate endogenous progenitor cells, we hypothesize that their use may offer a novel treatment strategy in frail patients.

The findings here replicate in large part the results of the earlier open label study, support the concept that MSCs have bioactivity against aging frailty, and confirm the fact that 100 million cells represents a superior dose level compared to 200 million. The reasons underlying the inverse dose relationship noted here remain incompletely understood. The 100 million dose group produced significant improvements in both physiologic and immunologic markers of frailty, while the high dose group solely demonstrated positive immunomodulatory effects.

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