Tolerogenic Human Dermal Fibroblasts (HDFS) Potential for Multiple Sclerosis Therapy: PRE-Clinical and Clinical Trial Study Results

Background: MS is a T cell-mediated autoimmune disorder targeting the myelin sheath. While the FDA has approved a number of small molecules and monoclonal antibodies for reduction of the relapse rate, severity of relapse, and rate of progression of MS, they all carry short and long term side effects that can impact the quality of life and overall health of the patients.

Objectives: While publications and clinical trials indicating the use of mesenchymal stem cells (MSCs) for autoimmune disorders are abound, publications utilizing fibroblasts for autoimmune diseases, which share many of the characteristics of MSCs, have been few and far between. Like MSCs, fibroblasts have the capacity for differentiation into several other cell types, can be prepared to be tolerogenic, have been studied extensively for wound healing, and have demonstrated tissue regeneration and immune modulation activities. However, unlike MSCs, HDFs are more abundant, are easier to source, have a faster doubling rate, and are far cheaper and easier to culture.

Methods: We carried out extensive in vitro and in vivo pre-clinical studies of tolerogenic HDFs in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. for our phase 0/1 clinical trial, our primary safety clinical trial studied a single-dose infusion of tolerogenic HDFs into four relapsing-remitting and one secondary progressive MS patient.

Results: Our in vivo results demonstrate that tolerogenic HDFs can suppress pathogenic T cell activation, stimulate T regulatory (Treg) cell expansion, inhibit dendritic cells (DC) maturation, stimulate oligodendrocyte expansion and myelin protein expression. Our results also demonstrate that administration of HDFs in the EAE model of MS led to a Treg-dependent disease inhibition that was significantly better than adipose or bone marrow-derived MSCs. Our safety clinical trial primary outcome indicated no adverse safety events during the study. additionally, our results indicated a strong correlation for CBC, blood chemistry, and electrocardiogram data for all patients when comparing to pre-infusion test results. Our secondary outcome efficacy data indicate a clinically significant improvement in PSAT and Nine-Hole Peg Tests, with no further deterioration noted in the Timed 25-foot Walk Test or EDSS. Gadolinium Enhanced MRI results of the patients also did not indicate any change in MRI as compared to pre-infusion baseline.

Conclusions: We are very encouraged by the promising results of our pre-clinical and safety-centered limited clinical trial data for the single-dose infusion of tolerogenic HDFs. We are in the process of submission for an IND to further study the safety and efficacy of various concentrations of HDFs and the impact of multiple-dose infusion of HDFs during an eighteen-month study period.