Feasibility Study of Tolerogenic Fibroblasts in Patients With Refractory Multiple Sclerosis

Fibroblasts have demonstrated potent immune modulatory and therapeutic activity in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, as well as in other models of autoimmune and inflammatory diseases.

This study will assess primary safety and secondary efficacy endpoints of intravenous administration of 100 million tolerogenic fibroblasts to 5 patients with relapsing remitting MS resistant to interferon. While the safety of fibroblasts administered clinically is established, it is unknown whether these cells are effective in the treatment of multiple sclerosis (MS).

Our hypothesis is that the tolerogenic fibroblasts will be well-tolerated and meet our primary objective. In addition, The investigators are optimistic that they will see signs of efficacy based on the following: Neurological assessment of the MS functional composite assessment which comprises of EDSS, the expanded EDSS (Rating Neurologic Impairment in Multiple Sclerosis, the Scripps neurological rating scale (NRS), paced auditory serial addition test (PASAT), the nine-hole peg test, and 25-foot walking time, short-form 36 (SF-36) quality of life questionnaire and gadolinium-enhanced MRI scans of the brain and cervical spinal cord.

Fibroblasts have demonstrated potent immune modulatory and therapeutic activity in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, as well as in other models of autoimmune and inflammatory diseases. Mechanistically, tolerogenic fibroblasts produce anti-inflammatory and immune modulatory factors, which appear to be therapeutic in the context of autoimmunity, including IL-10 and TGF-beta. Additionally, tolerogenic fibroblasts produce neurotrophic mediators that enhance myelin production and/or prevent neuronal apoptosis.

This study will assess primary safety and secondary efficacy endpoints of intravenous administration of 100 million tolerogenic fibroblasts to 5 patients with relapsing remitting MS resistant to interferon. While the safety of fibroblasts administered clinically is established, it is unknown whether these cells are effective in the treatment of multiple sclerosis (MS).

Research Hypothesis: Intravenous administration of 100 million tolerogenic fibroblasts will be well tolerated and induce a therapeutic effect in relapse remitting MS patients.

Rationale: The family of Mesenchymal Stem Cells (MSCs) is immune-modulatory, and bone marrow MSCs (BM-MSCs) have induced therapeutic responses in patients with MS \[1\]. Tolerogenic fibroblasts possess superior immune modulatory activity compared to BM-MSCs and adipose MSCs. The investigators, therefore, seek to perform a five-patient trial to assess the safety and signs of efficacy of this cell population in MS patients resistant to interferon.

The trial's primary objective is freedom from treatment-associated adverse events at 1, 2, 4, 8, and 16 weeks post-treatment. The study's secondary objective will be efficacy as assessed at baseline, weeks 2, 4, 8, and 16. The results will be quantified based on the following: Neurological assessment of the MS functional composite assessment, which comprises of EDSS, the expanded EDSS (Rating Neurologic Impairment in Multiple Sclerosis, the Scripps neurological rating scale (NRS), paced auditory serial addition test (PASAT), the nine-hole peg test, and 25-foot walking time, short-form 36 (SF-36) quality of life questionnaire and gadolinium-enhanced MRI scans of the brain and cervical spinal cord.

Eligibility Criteria:
Inclusion Criteria:

1. Patients willing to sign an informed consent and capable of understanding the features of this clinical trial.
2. Willing to keep a weekly diary and undergo observation for four months
3. Non-pregnant patients 18-55 years of age with MS according to the revised McDonald criteria and meeting the Possner criteria for clinically defined MS.
4. EDSS scores of 2·0 to 5·5 points assessed at least three months after the last acute attack of MS.

Exclusion Criteria:

1. Patients with evidence of active proliferative retinopathy.
2. Patients with poorly controlled diabetes mellitus (HbA1C \> 8.5%).
3. Patients with renal insufficiency (Creatinine \> 2.5) or failure.
4. Infection as evidenced by WBC count of \>15,000 k/cumm and/or temperature \>38C.
5. History of organ transplant.
6. History of previous or active malignancy, except for localized cutaneous basal or squamous cell carcinoma or carcinoma in situ of the cervix
7. History of sickle cell anemia
8. Cardiovascular conditions:

   1. Exercise limiting angina ( Canadian Cardiovascular Society Class greater or equal to 3
   2. Congestive heart failure (New York Heart Association class greater or equal to 3
   3. Unstable angina
   4. Acute ST elevation myocardial infarction (MI) within one month
   5. Transient ischemic attack or stroke within one month
   6. Severe valvular disease