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There is an unmet need to develop therapies aimed at prevention or reversal of progression-related disability in MS. Therapies for progressive MS must overcome the varied aspects of disease pathology such as inflammatory demyelination, neurodegeneration, and astrogliosis (sclerosis, or scar formation). Since 2001, Dr. Sadiq has directed the center’s research efforts to investigate the use of stem cells as a repair strategy for progressive MS. Stem cells are unspecialized cells that have the ability to regenerate damaged tissue.
Since 2004, Dr. Violaine Harris and her research team have been investigating a population of adult stem cells from bone marrow called mesenchymal stem cell-derived neural progenitors (MSC-NPs) as a source of stem cells to promote repair and regeneration in progressive MS. MSC-NP cells have a number of properties that make them suitable as a cell transplantation therapy for MS:
1. MSC-NP cells are autologous, meaning they are derived from a patient’s own bone marrow. Autologous cells are recognized as ‘self’ and are thus not rejected by the body after transplantation.
2. The neural characteristics of MSC-NP cells are associated with a reduced potential for mesodermal differentiation making them more appropriate for transplantation into the brain (Harris et al 2012)
3. MSC-NP cells are capable of promoting repair in the brain and spinal cord by the release of specific proteins that modulate the immune response and encourage existing brain progenitor cells to mature and remyelinate (Harris et al 2012)
A proof-of-concept study of MSC-NP transplantation in the EAE mouse model of MS demonstrated the efficacy of this therapeutic approach (Harris et al 2012). The study found that multiple doses of MSC-NPs were necessary to reduce disease in the mice. Importantly, they showed that intrathecal delivery of the MSC-NP cells directly into the spinal fluid was a feasible and effective route of administration. The mechanisms involved in MSC-NP-mediated repair included creation of a tolerant CNS milieu as well as induction of resident host stem cell progenitors to differentiate. Current research is focused on understanding the mechanisms of MSC-NP-mediated repair. Dr. Harris and her team are utilizing in vitro and in vivo models to better understand the ability of MSC-NPs to affect immunomodulatory (modulation of specific immune responses) and trophic (promotion of mature brain cell types) mechanisms of repair. Recent RNA sequencing of MSC-NP cells has provided additional molecular insight into the gene signature of these cells, revealing an enrichment of genes involved in cell communication. The research has identified a panel of candidate growth factors and small extracellular vesicles (EVs) as mediators of the reparative response.
In 2013, the FDA approved the investigational new drug (IND) application to conduct an open-label Phase I clinical trial to test the safety and tolerability of intrathecal transplantation of autologous MSC-NP cells in 20 patients with progressive MS. Treatment in the first trial patient started in April 2014. Each of the 20 patients were administered 3 separate doses of up to 10 million MSC-NPs spaced 3 months apart. This was the only clinical trial of its kind in the United States to test freshly harvested MSC-NP cells administered intrathecally in a multiple dosing regimen (Harris and Sadiq 2015). In addition to safety outcomes, study patients were monitored for disability status (EDSS), muscle strength, walking speed, bladder function, and MRI. The most common minor adverse event included a headache and sometimes fever during the first 24 hours following the treatment, which was otherwise found to be safe and well-tolerated. Of the 20 study subjects, 15 (or 75%) demonstrated functional neurological improvement measured 3 months after the third treatment (Harris et al 2018). The improvements associated with IT-MSC-NP treatment were sustained for up to 2 years in a subset of patients, suggesting that some of the clinical benefits of MSC-NP treatment may be long-lasting (Harris et al 2021).
The encouraging safety and efficacy results from the phase I trial led the FDA and IRB to approve a larger Phase II placebo-controlled study to confirm efficacy of intrathecal MSC-NP treatment in patients with MS. A Phase II study is designed to study efficacy of a treatment by comparing to a placebo control. The Phase II study is double-blinded, meaning neither the patient nor the assessing neurologist knows whether or not the patient got a stem cell treatment or placebo. The study has a crossover design, meaning that study patients who received placebo in the first year will crossover into the MSC-NP treatment group in the second year (and vice versa). The study is fully enrolled with 50 MS patients and results are expected in 2022.
Due to the groundbreaking advancements being made with MSC-NP-based cell therapy in MS, Tisch MSRCNY opened the Regenerative Medicine Laboratory, a state-of-the-art cGMP cell production facility. The Regenerative Medicine Laboratory enables the manufacturing of clinical-grade doses of autologous MSC-NPs for cell therapy treatments in trial subjects with MS.