Subcutaneous Injection of Allogeneic Adipose-Derived Mesenchymal Stromal Cells in Psoriasis Plaques: Clinical Trial Phase I.

OBJECTIVE: Mesenchymal stromal cells (MSCs) play immunomodulatory role in various autoimmune diseases. Previous pre-clinical and clinical studies have shown that MSCs could be a therapeutic modality for psoriasis. However, the mechanisms of treatment and its possible side effects are under investigation. In this study, the safety and probable efficacy of injecting allogeneic adipose-derived mesenchymal stromal cells (ADSCs) in psoriatic patients were evaluated. MATERIALS AND METHODS: In this phase I clinical study with six months of follow-up, total number of 1×106 or 3×106 cells/cm2 of ADSCs were injected into the subcutaneous tissue of each plaque as a single dose in three males and two females (3M/2F) with a mean age of 32.8 ± 8.18. The primary outcome was safety. Changes in clinical and histological indexes, the number of B and T lymphocytes in local and peripheral blood, and serum levels of inflammatory cytokines were assessed. Paired t test was used to compare variables at two time points (baseline and six months after injection) and repeated measures ANOVA test was utilized for variables at three time points in follow-up visits. RESULTS: No major adverse effects such as burning, pain, itching, or any systemic side effects were observed following ADSCs injection, and the lesions showed slight to considerable improvement after injection. The mRNA expression levels of pro-inflammatory factors were reduced in the dermis of the patients after injection. The increased expression level of Foxp3 transcription factor in the patient blood samples suggested modulation of inflammation after ADMSCs administration. Six months after the intervention, no major side effects were reported, but skin thickness, erythema, and scaling of the plaques, as well as the PASI score, were decreased in majority of patients. CONCLUSION: Our study suggested that ADSC injection could be considered as a safe and effective therapeutic approach for psoriatic plaques (registration number: IRCT20080728001031N24).

Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial.

BACKGROUND: Type-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, mesenchymal stem cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients. METHODS: After receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and was followed for at least one-year post-transplantation. RESULTS: The results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices. CONCLUSIONS: Taken together, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes. TRIAL REGISTRATION: This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) ( https://en.irct.ir/trial/23256 ) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). ( https://clinicaltrials.gov/ct2/show/NCT04078308 ).

Mesenchymal Stromal Cell Therapy Improves Refractory Perianal Fistula in Crohn's Disease: Case Series Clinical Interventional Study.

Objective: Perianal fistulas in Crohn's disease (CD) are the main challenges in inflammatory bowel diseases (IBDs). Some of the fistulas are refractory to any therapeutic strategy. The aim of this study was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) as a novel promising modality for the treatment of fistulizing CD. Materials and Methods: This case series clinical interventional study was conducted from 2014 to 2017 at Shariati Hospital, an IBD referral center in Tehran, Iran. Refractory adult patients with CD who had draining perianal fistulas were enrolled in this study. All patients were examined by a colorectal surgeon and the fistula imaging studies were performed by pelvic magnetic resonance imaging (MRI). After autologous bone marrow (BM) aspiration and MSCs isolation, the cells were cultured and passaged under current good manufacturing practice (cGMP) conditions. Four intra-fistula injections of cells, each containing 40×106 MSCs suspended in fibrin glue, were administered by an expert surgeon every 4 weeks. Procedure safety, feasibility and closure of the perianal fistulas at week 24 were assessed. Clinical examination and MRI findings were considered as the primary end points. Results: In total, 5 patients (2 males and 3 females) were enrolled in this study. No adverse events were observed during the six-month follow-up in these patients. Both the Crohn's Disease Activity Index (CDAI) and Perianal Disease Activity Index (PDAI) scores decreased in all patients after cell injections and one patient achieved complete remission with closure of fistulas, discontinuation of fistula discharge, and closure of the external opening. Conclusion: Local injection of MSCs combined with fibrin glue is potentially a safe and effective therapeutic approach for complex perianal fistulas in patients with CD.

Autologous Muscle-derived Cell Injection for Treatment of Female Stress Urinary Incontinence: A Single- Arm Clinical Trial with 24-months Follow-Up.

PURPOSE: This clinical study evaluated the effect of autologous muscle-derived cell (MDC) injection for the treat-ment of female patients with pure stress urinary incontinence (SUI). MATERIALS AND METHODS: A total of 20 women with SUI received transurethral injections of autologous MDCs. Baseline and follow-up evaluations consisted of physical examinations (cough stress tests), one-hour pad test, In-continence Impact Questionnaire-7 (IIQ-7), and Urogenital Distress Inventory (UDI-6) scoring. The patients were followed one week as well as 1, 3, 6, 9, 12, and 24 month(s) after the procedure. Multichannel urodynamic study were performed before and 24 months after the intervention. The incidence and severity of adverse events (AE) were also recorded at each follow-up visit. RESULTS: A total of 20 eligible female patients with the chief complaint of SUI that was unresponsive to conserva-tive management, was enrolled in the trial, 17 of whom completed all follow-up visits. At 12th months, 10 (59%) patients had complete response, whereas 2 (12%) and 5 (29%) patients had partial and no response, respectively. At 24th months, relapse of SUI in 5 out of 10 complete responders (29%) and 2 out of 2 partial responders to the treatment, respectively. The intervention produced no serious AE during the trial. CONCLUSION: According to our results, though obtained from a limited number of patients, MDC therapy was a minimally invasive and safe procedure for treatment of female patients with pure SUI. However, currently, the efficacy of this type of treatment for SUI is not sufficiently high and multi-center randomized clinical trials are required to be conducted before reaching a concrete conclusion.

Systemic Infusion of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in Peritoneal Dialysis Patients: Feasibility and Safety.

OBJECTIVE: Using mesenchymal stem cells (MSCs) is regarded as a new therapeutic approach for improving fibrotic diseases. the aim of this study to evaluate the feasibility and safety of systemic infusion of autologous adipose tissue-derived MSCs (AD-MSCs) in peritoneal dialysis (PD) patients with expected peritoneal fibrosis. MATERIALS AND METHODS: This study was a prospective, open-label, non-randomized, placebo-free, phase I clinical trial. Case group consisted of nine eligible renal failure patients with more than two years of history of being on PD. Autologous AD-MSCs were obtained through lipoaspiration and expanded under good manufacturing practice conditions. Patients received 1.2 ± 0.1×106 cell/kg of AD-MSCs via cubital vein and then were followed for six months at time points of baseline, and then 3 weeks, 6 weeks, 12 weeks, 16 weeks and 24 weeks after infusion. Clinical, biochemical and peritoneal equilibration test (PET) were performed to assess the safety and probable change in peritoneal solute transport parameters. RESULTS: No serious adverse events and no catheter-related complications were found in the participants. 14 minor reported adverse events were self-limited or subsided after supportive treatment. One patient developed an episode of peritonitis and another patient experienced exit site infection, which did not appear to be related to the procedure. A significant decrease in the rate of solute transport across peritoneal membrane was detected by PET (D/P cr=0.77 vs. 0.73, P=0.02). CONCLUSION: This study, for the first time, showed the feasibility and safety of AD-MSCs in PD patients and the potentials for positive changes in solute transport. Further studies with larger samples, longer follow-up, and randomized blind control groups to elucidate the most effective route, frequency and dose of MSCs administration, are necessary (Registration Number: IRCT2015052415841N2).

Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: The intra-articular implantation of mesenchymal stromal cells (MSCs) as a treatment for knee osteoarthritis (OA) is an emerging new therapy. In this study, patients with knee OA received intra-articular implantations of autologous bone marrow-derived MSCs. We sought to assess the safety and efficacy of this implantation. MATERIALS AND METHODS: This was a phase 1/2 single-center, triple-blind, randomized controlled trial (RCT) with a placebo control. The subjects consisted of patients with knee OA randomly assigned to either an intra-articular implantation of MSCs (40 × 106 cells) or 5 mL normal saline (placebo). Patients were followed up for 6 months after the implantations. The pain level and function improvements for patient-reported outcomes were assessed based on a visual analog scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and its subscales, walking distance, painless walking distance, standing time and knee flexion compared with the placebo group at 3 and 6 months following the implantations. RESULTS: Overall, 43 patients (Kellgren-Lawrence grades 2, 3 and 4) were assigned to either the MSCs (n = 19) or placebo (n = 24) group. Patients who received MSCs experienced significantly greater improvements in WOMAC total score, WOMAC pain and physical function subscales and painless walking distance compared with patients who received placebo. There were no major adverse events attributed to the MSC therapy. CONCLUSION: This randomized, triple-blind, placebo-controlled RCT demonstrated the safety and efficacy of a single intra-articular implantation of 40 × 106 autologous MSCs in patients with knee OA. Intra-articular implantation of MSCs provided significant and clinically relevant pain relief over 6 months versus placebo and could be considered a promising novel treatment for knee OA. We propose that further investigations should be conducted over an extended assessment period and with a larger cohort.

Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo-controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement.

Safety and tolerability of autologous bone marrow mesenchymal stromal cells in ADPKD patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually develop end-stage renal disease (ESRD). We hypothesize that bone marrow mesenchymal stromal cells (BMMSCs) are renotropic and may improve kidney function via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. In this study, we aim to assess the safety and tolerability of a BMMSC infusion in ADPKD patients. METHODS: We performed a single-arm phase I clinical trial with a 12-month follow-up. This study enrolled six eligible ADPKD patients with an estimated glomerular filtration rate (eGFR) of 25-60 ml/min/1.73 m2. Patients received autologous cultured BMMSCs (2 × 106 cells/kg) through the cubital vein according to our infusion protocol. We investigated safety issues and kidney function during the follow-up visits, and compared the findings to baseline and 1 year prior to the intervention. RESULTS: There were no patients lost to follow-up. We observed no cell-related adverse events (AE) and serious adverse events (SAE) after 12 months of follow-up. The mean eGFR value of 33.8 ± 5.3 ml/min/1.73 m2 1 year before cell infusion declined to 26.7 ± 3.1 ml/min/1.73 m2 at baseline (P = 0.03) and 25.8 ± 6.2 ml/min/1.73 m2 at the 12-month follow-up visit (P = 0.62). The mean serum creatinine (SCr) level of 2 ± 0.3 mg/dl 1 year before the infusion increased to 2.5 ± 0.4 mg/dl at baseline (P = 0.04) and 2.5 ± 0.6 mg/dl at the 12-month follow-up (P = 0.96). This indicated significant changes between the differences of these two periods (12 months before infusion to baseline, and 12 months after infusion to baseline) in SCr (P = 0.05), but not eGFR (P = 0.09). CONCLUSIONS: This trial demonstrated the safety and tolerability of an intravenous transplantation of autologous BMMSCs. BMMSC efficacy in ADPKD patients should be investigated in a randomized placebo-controlled trial with a larger population, which we intend to perform. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02166489 . Registered on June 14, 2014.

Effect of autologous muscle-derived cells in the treatment of urinary incontinence in female patients with intrinsic sphincter deficiency and epispadias: A prospective study.

OBJECTIVES: To evaluate the effect of autologous muscle-derived cells injection in the treatment of complicated stress urinary incontinence in female patients. METHODS: Female patients presenting with severe and complicated stress urinary incontinence secondary to the bladder neck and/or urethral trauma or congenital epispadias (with or without exstrophy) were enrolled in this prospective study. They underwent transurethral injection of autologous muscle-derived cells. In selected cases, another injection was given after 6 months, as per the surgeon's assessment. All patients were monitored for 1 year, and the effect of autologous muscle-derived cells was evaluated by cough stress test, 1-h pad test and Incontinence Impact Questionnaire-short form score. A multichannel urodynamic study and maximum urethral closure pressure were carried out before and 12 months after the last treatment session. Cough stress test, 1-h pad test and uroflowmetry were repeated 36 months after the last injection. Severity and occurrence of complications were recorded at each visit. RESULTS: All 10 patients who completed the study were monitored for 36 months. Three patients were cured, four had improved and three did not respond to the treatment. There was no major adverse effect related to the treatment. CONCLUSIONS: Muscle-derived cell therapy might represent a minimally-invasive and a safe procedure in the treatment of patients with severe and complicated stress urinary incontinence.