Stem Cell Therapies for Epidermolysis Bullosa Treatment
Abstract
:1. Introduction
2. Types of Epidermolysis Bullosa
2.1. Epidermolysis Bullosa Simplex (EBS)
2.2. Junctional Epidermolysis Bullosa (JEB)
2.3. Dystrophic Epidermolysis Bullosa (DEB)
2.4. Mixed Epidermolysis Bullosa—Kindler Syndrome
3. Introduction to Stem Cells
- Totipotent Cells: They have the ability to differentiate into all possible cell types. For example, a fertilized oocyte and the first few cells that result from the division of the zygote are totipotent cells [32].
- Pluripotent Cells: They have the ability to differentiate into cells that come from the 3 germ layers—ectoderm, endoderm, and mesoderm—from which all tissues and organs derive [33]. Examples include embryonic stem cells (ESCs), as well as induced pluripotent stem cells (iPSCs) which arise from reprogramming somatic cells [34].
- Oligopotent Cells: They have the ability to differentiate into a few lineages within a single tissue. This category includes hematopoietic stem cells (HSCs) which can differentiate into lymphoid or myeloid stem cells [38].
- Unipotent Cells: They have the ability to only produce cells of their own type, such as muscle stem cells which can differentiate into only mature muscle cells [39].
- As for the classification based on their origin, stem cells can be classified as below:
- Adult Stem Cells: they come from the “niches” in adult tissues. They are characterized as multipotent because they can self-renew, but have a low ability to differentiate. They can mature in cells of the tissue or organ from which they originate but also play a key role in their maintenance and repair [40].
- Advanced Perinatal embryonic stem cells: Perinatal stem cells (e.g., from aborted embryos or umbilical cord blood). They are the various types of stem cells found in the umbilical cord unit, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), amniotic epithelial cells (AMSCs), chorionic mesenchymal stem cells (CMSCs) and progenitor endothelial stem cells, as well as earlier cell types such as unrestricted somatic stem cells (USSCs) and very small embryonic-like cells (Very Small Embryonic Like Stem Cells, VSELs). The majority of the scientific community characterizes them as pluripotent and not simply as multipotent cells, which gives them the characteristic of the so-called plasticity of these stem cells and has led to a wide range of clinical applications [41].
- Embryonic stem cells: Embryonic cells that arise during the first four days after fertilization are considered totipotent and form all the cells of the embryo as well as extraembryonic formations, such as the placenta. Embryonic stem cells that arise after four to five days are considered pluripotent, they come from inside the blastocyst and can transform into all cell types of an organism [42]. A third class of “embryonic” cells, so-called induced pluripotent cells (iPSCs), has been added in recent years. iPSCs are developed through the genetic manipulation of differentiated cells [43].
4. Cellular Therapy Options for EB
4.1. Hematopoietic Stem Cells (HSCs) Transplantation
4.2. Cytotherapies with Mesenchymal Stem Cells (MSCs)
4.3. Genetically Corrected Autologous Epidermal Stem Cell and Fibroblasts Therapies
4.4. Induced Pluripotent Stem Cells (iPSs)
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
EB | Epidermolysis bullosa |
EBS | Epidermolysis bullosa simplex |
ECM | extracellular matrix |
JEB | Epidermolysis bullosa conjunctiva |
JEB-H | Epidermolysis Bullosa Herlitz |
JEB-nH | Epidermolysis bullosa non-Herlitz |
LOC syndrome | Laryngo-onycho-cutaneous syndrome |
DEB | Dystrophic epidermolysis bullosa |
DDEB | Autosomal dominant dystrophic epidermolysis bullosa |
RDEB | Autosomal recessive dystrophic epidermolysis bullosa |
MSCs | Mesenchymal stem cells |
HCs | hematopoietic stem cells |
BM | Bone marrow |
BMT | Bone marrow transplantation |
iPSs | Induced pluripotent stem cells |
COLVII | Collagen type VII |
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Classification | Cell Type | Differentiation | Examples |
---|---|---|---|
Totipotent | Embryonic stem cells | Differentiate into any cell type | Zygotes |
Pluripotent | Advanced Perinatal embryonic stem cells | Differentiate into of all three germ layers | ECSs, AMSCs, CMSCs, USSCs, iPSCs, VSELs |
Multipotent | Adult stem cells | Differentiate into a limited range of cell types | MSCs, HSCs |
Oligopotent | Adult stem cells | Differentiate into a limited range of cell types | Lymphoid, Myeloid |
Unipotent | Adult stem cells | Differentiate into a single type cell type | Epidermal |
Title/Clinical Trial Identifier | Phase/Status | Condition | Interventions/Cell Types | Safety | Outcome | Country |
---|---|---|---|---|---|---|
NCT03529877: Allogeneic ABCB5-positive Stem Cells for Treatment of Epidermolysis Bullosa [47] | Phase I/II, International, multicentric, single-arm. Completed | RDEB | Intravenous infusion of allogeneic ABCB5+ MSCs | Good tolerability, manageable safety. Adverse effects: (1) mild lymphadenopathy (1 out of 16), (2) hypersensitivity reactions (2 out of 16). | Significant reductions in EB disease activity and scarring index activity. Reductions in pain and itch. | United States (US), Austria, France, German, Italy, United Kingdom (UK) |
NCT04153630: Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow | Phase I/II, pilot, single group, open-label. Unknown status | RDEB | Systemic infusion of BM-MSCs from haploidentical donor. Intravenous injection with a dose of 2–3 × 106 cells/kg. | Unknown | Unknown | Spain |
NCT04520022: Safety and Effectiveness Study of Allogeneic Umbilical Cord Blood-derived Mesenchymal Stem Cell [46] | Phase I/II, single-group, single-center, open-label. Completed. | RDEB | Intravenous administrations of allogeneic hUCB-MSCs, 3 × 106 cells/kg, total of 3 doses every 2 weeks. | Well-tolerated, no severe adverse events. | Improvements in the EB severity score, body surface area involvement, blister counts, pain, pruritus and quality of life. Increase of collagen type VII expression at the DEJ in 1 out of 6 patients. | Korea |
NCT02579369: Study to Evaluate the Safety of ALLO-ASC-DFU in the Subjects With Dystrophic Epidermolysis Bullosa | Phase I/II, non-randomized, parallel assignment, open-label. Unknown status | RDEB | Application of hydrogel dressing for RDEB wound with allogeneic AT-MSCs | Unknown | Unknown | Korea |
NCT00478244: Allogeneic hematopoietic cell transplantation to correct the biochemical defect and create tolerance to donor tissue in subjects with EB [50]. | Single group, open-label. Terminated (Competing studies). | RDEB | Immunomyeloablative chemotherapy and allogeneic hematopoietic stem cell transplantation | One of six patients died as a consequence of graft rejection and infection after 2 years. High-risk therapeutic approach for patients with less severe RDEB. | Increased collagen VII deposition at the DEJ in 5 of 5 recipients without normalization of anchoring fibrils and reduced blistering. | US |
NCT03183934: A Follow-up Study to Evaluate the Efficacy and Safety of ALLO-ASC-DFU in ALLO-ASC-EB-101 Clinical Trial | Follow-up study | Application of dressing for DEB with allogeneic AT-MSCs | Unknown | Unknown | Korea | |
NCT00881556: A pilot study of reduced intensity conditioning (RIC) and allogeneic stem cell transplantation (ALLOSCT) in children with RDEB. | Early phase I, single group, open-label. Terminated | RDEB | Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (AlloSCT) from family-related donors and unrelated cord blood (UCB) donors will be safe and well tolerated in selected patients with RDEB. | Unknown | Unknown | U.S. |
NCT02582775: Biochemical Correction of Severe EB by Allo HSCT and Serial Donor MSCs [51] | Phase II, Non-randomized, open-label, Active, not recruiting | Severe, generalized RDEB | Epidermolysis bullosa patients treated with chemotherapy and BM-HSC transplant with BM-MSCs infusions | Improved safety due to PTCγ treatment. | Improved Col VII and restoration of anchoring fibrils, reduced erosions. | U.S |
NCT01033552: Biochemical Correction of Severe EB by Allo HSCT and “Off-the-shelf” MSCs | Phase I/II, single group, open-label. Completed | Severe EB | Mesenchymal stem cell transplantation infused intravenously and bone marrow or umbilical cord blood products infusion. | Unknown | Unknow | U.S. |
NCT02323789: Mesenchymal allogeneic stromal cells in adults with RDEB (ADSTEM) [52] | Phase I/II, Open-label, Unknown status | RDEB | Intravenous alloegeneic mesenchymal stromal cell (BM-MSCs) therapy in adults with RDEB | No serious adverse events up to 12 months. Requirement for monitoring possible development or progression of squamous cell carcinoma (SCC). | Transient reduction in disease activity scores and significant reduction in itch. Transient increase in type VII collagen at 1 out of 10 participants. | U.K. |
2012-00894-87: Allogeneic mesenchymal stromal cells for the treatment of skin disease in children with recessive dystrophic epidermolysis bullosa [53] | Phase I/II, Non-randomized-controlled, single arm. Completed | RDEB | 3 intravenous allogeneic BM-MSC infusions | Good tolerance | Decrease in global severity score, increase in quality of life, decrease in blister counts. | U.K. |
NCT05111600: Open-label, Pivotal Clinical Trial to Confirm Efficacy and Safety of Autologous Grafts Containing Stem Cells Genetically Modified for Epidermis Restoration in Patients With Junctional Epidermolysis Bullosa (HOLOGENE 5) [54]. | Phase II/III, Prospective, multicenter and multinational, open-label, uncontrolled. Recruiting | JEB Non Herlitz type | Grafting of fibrin-cultured epidermal sheets generated by transgenic clonogenic keratinocytes, including epidermal stem cells | Promising safety profile | Most likely permanent functional restoration of the dermo-epidermal junction, long-lasting ie engrafted transgenic epidermal stem cells allowing continuous self-renewal | Italy, France |
NCT02493816: Phase I Study of Lentiviral-mediated COL7A1 Gene-modified Autologous Fibroblasts in adults with Recessive Dystrophic Epidermolysis Bullosa [55]. | Phase I, open-label. Completed | RDEB | Lentiviral-mediated COL7A1 gene-modified autologous fibroblasts, 3 intra-dernal injections on day 0 only | Safe, only mild local injection procedure-related side effects lasting for a few hours without requiring treatment | Significant increase in collagen VII expression at the derm-epidermla junction but not associated with mature anchoring filaments, improvement of healing. | UK |
NCT02810951: A Phase I/II Study of FCX-007 (Genetically-Modified Autologous Human Dermal Fibroblasts) for Recessive Dystrophic Epidermolysis Bullosa (RDEB) [56]. | Phase I/II, single group, opne-label. Terminated | RDEB | FCX-007 is a genetically modified cell product obtained from the subject’s own skin cells (Autologous fibroblasts). The cells are expanded and genetically modified to produce functional COL7. FCX-007 cell suspension is injected intradermally. | |||
NCT03490331: Clinical trial to assess the safety and efficacy of autologous cultured epidermal grafts containing epidermal stem cells genetically modified with a gamma-retroviral (rv) vector carrying COL17A1 cDNA for restoration of epidermis in patients with junctional epidermolysis bullosa | Phase I/II, prospective, open-label, uncontrolled. Terminated (No patient ongoing (none completed the study). Changes to the viral vector ongoing) | JEB | Transplantation surgery of genetically corrected cultured epidermal autograft. | Unknown | Unknown | Austria |
NCT02984085: Clinical trial to assess the safety and efficacy of autologous cultured epidermal grafts containing epidermal stem cells genetically modified with a gamma-retroviral (rv) vector carrying COL7A1 cDNA for restoration of epidermis in patients with recessive dystrophic epidermolysis bullosa. | Phase I/II, prospective, open-label, uncontrolled. Terminated (replaced by study in progress) | RDEB | Transplantation surgery of genetically corrected cultured epidermal autograft. | Unknown | Unknown | |
NCT04186650: Ex vivo gene therapy linical trial for RDEB using genetically corrected autologous skin equivalents (EBGraft). | Phase I/II, non-randomized single-group, open—label. Active, not recruiting | RDEB | Graft of SIN RV-mediated COL7A1 gene-modified autologous skin equivalent | - | - | France |
NCT01263379: Gene transfer for recessive dystophic epidrmolysis bullosa [57,58,59] | Phase I/II, single-center, open-label. Active, not recruiting. | RDEB | Gene transfer for RDEB using the drug LZRSE-Col7A1 engineered autologous epidermal sheets (EB-101) | Safe, no serious adverse effects during up to 8 years. 2 adult patients out of 10 developed SCC on anatomic sites distant form grafted sites. | Long-term improvements in wound healing, pain and itch. Some grafts showed collagen VII expression in anchoring fibrils. Collagen VII expression persisted up to 2 years after treatment in 2 participants. | US |
NCT04227106: A phase 3 study of EB-101 for the treatment of RDEB. | Phase III, single-group, open-label. Completed | RDEB | One-time surgical application of EB-101 on up to 6 chronic RDEB wounds. | Unknown | Unknown | US |
NCT051116000: Open-label, pivotal clinical trial to confirm efficacy and safety of autologous grafts containing stem cells genetically modified for epidermis restoration in patients with JEB (HOLOGENE 5). | Phase II/III, prospective, multicenter and multinational, open-label, uncontrolled. | JEB | Transplantation of autologous cultured epidermal grafts containing epidermal stem cells genetically modified transduced with a LAMB3-gamma retroviral vector. | In progress | In progress | France, Italy. |
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Niti, A.; Koliakos, G.; Michopoulou, A. Stem Cell Therapies for Epidermolysis Bullosa Treatment. Bioengineering 2023, 10, 422. https://doi.org/10.3390/bioengineering10040422
Niti A, Koliakos G, Michopoulou A. Stem Cell Therapies for Epidermolysis Bullosa Treatment. Bioengineering. 2023; 10(4):422. https://doi.org/10.3390/bioengineering10040422
Chicago/Turabian StyleNiti, Argyrw, Georgios Koliakos, and Anna Michopoulou. 2023. "Stem Cell Therapies for Epidermolysis Bullosa Treatment" Bioengineering 10, no. 4: 422. https://doi.org/10.3390/bioengineering10040422