TABLE 5.
Preclinical in vivo and clinical studies of hMSCs used as advanced therapy for recessive dystrophic epidermolysis bullosa in the last 5 years.
| PRECLINICAL IN VIVO STUDIES | |||||||||||
| Type of Advanced Therapy | Cells | Disease model and Treatments | Animals | Type of wound analyzed | Follow-up | References | |||||
| Cell therapy | hBM-MSCs | 1–8 h after wounding, 2 × 106 hBM-MSCs were injected at the wound edges and this procedure was repeated 48 h after the first injection 2–8 h after wounding, PBS alone were injected at the wound edges and this procedure was repeated 48 h after the first injection | C7-hypomorphic mice and wild-type littermates | Two full thickness skin wounds were incised at the mid-back | 12 weeks | Kühl et al., 2015 | |||||
| Tissue engineering, cell therapy and gene therapy | hUCB-MSCs | 1-Skin substitute constituted of RDEB fibroblasts mixed with COL7A1-transduced MSCs at a 1:1 ratio. Primary RDEB keratinocytes were then seeded on top 2-Skin substitute constituted of RDEB fibroblasts alone. Primary RDEB keratinocytes were then seeded on top 3-Skin substitute constituted of wild type fibroblasts alone. Wild type keratinocytes were then seeded on top 4-After 6–8 weeks mice treated with human skin substitutes received two intradermal injections of 0.5 × 106 engineered MSCs in 50 ul buffered saline solution each or injected with 2 × 106 engineered MSCs in 150 ul buffered saline solution via tail vein. Controls without cells were also injected | 7 Immunod- eficient NOD-scid IL2Rgammanull mice | Full-thickness wound followed by devitalization of mouse skin | 8–10 weeks | Petrova et al., 2020 | |||||
| CLINICAL STUDIES | |||||||||||
| Type of advanced therapy | Cells | Type of clinical study | N (male/female) | Age (years)a | hMSC treatment | Safety (Treatment-related adverse events) | Total Body Surface Area (TBSA) affecteda | Effectivenessa | Follow-upa | References | |
| Cell therapy | Allogeneic hBM-MSCs | Phase I/II Clinical Trial (Single Group Assignment- Open Label) | 10 (5/5) | 4.8 ± 3.8 (1–11) | Three intravenous infusions of hBM-MSCs on Days 0, 7, and 28, at a dose of 1× 106 to 3 × 106 cells/kg | 78% of adverse events were not related to the hBM-MSCs infusions 2 severe events of DMSO odor Mild nausea and abdominal pain and bradycardia were observed during 2 infusions (each) | 23.2 ± 11.2% | Mean quality of life score (higher is worse) reported by parents was 41.9 at baseline vs. 39.0 at day 180 | 180 days | Petrof et al., 2015 | |
| Allogeneic hBM-MSCs | Randomized clinical trial (parallel assignment- double blind) | 7 (3/4) | 3.8 ± 2 (1–6) | Cyclosporine suspension in a dose of 5 mg/kg per day Intravenous injection of hBM-MSCs (from 70 to 150 × 106 cells/patient) | None | 67.1 ± 11.1% (50–80%) | The mean number of new blister formation decreased significantly after treatment from 43 ± 21.2 to 9 ± 10.97 in cyclosporine’s group and from 49 ± 1.8 to 13 ± 8.5 in placebo’s group | 1 year | El-Darouti et al., 2016 | ||
| 7 (3/4) | 7.7 ± 6.4 (2–20) | Placebo suspension without cyclosporine Intravenous injection of hBM-MSCs (from 70 to 150 × 106 cells/patient) | 64.3 ± 18.1% (40–80%) | ||||||||
| Allogeneic hBM-MSCs | Phase II Clinical Trial | 10 (5/5) | 9.1 ± 7 (1.8–22.1) | hBM-MSCs infusions | 16% of transplants complicated by veno-occlusive disease of the liver Low rates of acute (0%) and chronic (10%, n = 1) graft versus host disease | 49.5% | Reduction of surface area of blisters/erosion to 27.5% | 1 year | (Ebens et al., 2019) NCT02582775 (MT2015-20: Biochemical Correction of Severe EB by Allo HSCT and Serial Donor MSCs – Full Text View – ClinicalTrials.gov)3 | ||
| Allogeneic hBM-MSCs | Phase I/II Clinical Trial (Single Group Assignment- Open Label) | 10 (5/5) | 36.1 ± 9 (26–55) | 2 intravenous infusions of hBM-MSCs (24 × 106 to 4 × 106 cells/kg) | None | - | There was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch | 1 year | (Rashidghamat et al., 2020) NCT02323789 (Mesenchymal Stromal Cells in Adults With Recessive Dystrophic Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov)2 | ||
| Allogeneic hUCB-MSCs | Phase I/II Clinical Trial (Single Group Assignment- Open Label) | 5 | (10–60) | Intravenous injection of 3 doses of 3 × 106 cells/kg | – | − | No results posted | 8 months | NCT04520022 (Safety and Effectiveness Study of Allogeneic Umbilical Cord Blood-derived Mesenchymal Stem Cell in Patients With RDEB – Full Text View – ClinicalTrials.gov)4 | ||
| Allogeneic haploidentical hBM-MSCs | Phase I/II Clinical Trial (Single Group Assignment- Open Label) | 9 | (1–18) | Intravenous injection of 3 doses of 2× 106 to 3 × 106 cells/kg | − | − | No results posted | 5 years | NCT04153630 (Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov)5 | ||
| Allogeneic hMSCs (not defined) | Phase I/IIa Multicenter Clinical Trial (Single Group Assignment- Open Label) | 16 | Up to 55 | Intravenous injection of 3 doses of 2 × 106 cells/kg | – | − | No results posted | 24 months | NCT03529877 (Allogeneic ABCB5-positive Stem Cells for Treatment of Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov)1 | ||
aExpression of measures: mean ± standard deviation (range).
1Allogeneic ABCB5-positive Stem Cells for Treatment of Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov Available at: https://www.clinicaltrials.gov/ct2/show/NCT03529877?term=mesenchymal+stem+cells&recrs=abdefgh&cond=Recessive+Dystrophic+Epidermolysis+Bullosa&strd_s=01%2F01%2F2015&strd_e=12%2F31%2F2020&draw=2&rank=3 [Accessed January 13, 2021].
2Mesenchymal Stromal Cells in Adults With Recessive Dystrophic Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov Available at: https://clinicaltrials.gov/ct2/show/NCT02323789 [Accessed February 14, 2021].
3MT2015-20: Biochemical Correction of Severe EB by Allo HSCT and Serial Donor MSCs – Full Text View – ClinicalTrials.gov Available at: https://clinicaltrials.gov/ct2/show/NCT02582775 [Accessed February 14, 2021].
4Safety and Effectiveness Study of Allogeneic Umbilical Cord Blood-derived Mesenchymal Stem Cell in Patients With RDEB – Full Text View – ClinicalTrials.gov Available at: https://www.clinicaltrials.gov/ct2/show/NCT04520022?term=mesenchymal+stem+cells&recrs=abdefgh&cond=Recessive+Dystrophic+Epidermolysis+Bullosa&strd_s=01%2F01%2F2015&strd_e=12%2F31%2F2020&draw=2&rank=1 [Accessed January 13, 2021].
5Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa – Full Text View – ClinicalTrials.gov Available at: https://www.clinicaltrials.gov/ct2/show/NCT04153630?term=mesenchymal+stem+cells&recrs=abdefgh&cond=Recessive+Dystrophic+Epidermolysis+Bullosa&strd_s=01%2F01%2F2015&strd_e=12%2F31%2F2020&draw=2&rank=2 [Accessed January 13, 2021].