Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa

Abstract

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds.

Methods: Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks.

Results: Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up.

Conclusions: Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming.

Trial registration: ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://ichgcp.net/clinical-trials-registry/NCT01263379.

Keywords: Blistering diseases; Clinical trials; Epidermolysis bullosa; Gene therapy; Genetic diseases; Genodermatoses; Recessive dystrophic epidermolysis bullosa.

Conflict of interest statement

ASC, JYT, and MPM are clinical investigators for Abeona Therapeutics, Inc and Phoenix Tissue Repair. JYT is a stockholder and consultant to BridgeBio and PellePharm, Inc. ASC and JYT are also clinical investigators for Biomendics, LLC. MPM is also a clinical investigator for WINGS, Castle Creek Pharmaceuticals, and Krystal Biotech.

© 2022. The Author(s).

Figures

Fig. 1

Clinical wound healing by investigator global assessment (IGA) of chronic wounds treated with gene-corrected autologous keratinocyte grafts[a]. [a] A red box indicates < 50% wound healing compared to baseline, a yellow box indicates 50–74% wound healing compared to baseline, and a green box indicates ≥ 75% wound healing compared to baseline. A grey box indicates that the follow-up visit was conducted virtually due to the ongoing SARS-CoV 2 pandemic, which precluded Investigator Global Assessment (IGA) of wound healing. A striped box indicates a missed appointment. A white box indicates prospective dates. Wounds A-F were chronic wounds. Wound Z was an induced wound. Control wounds are not included. [b] Subjects 4 and 5 died prior to their year six and year five visits, respectively

Fig. 2

Representative photographs of chronic open RDEB wounds before and after treatment with gene-corrected autologous keratinocyte grafts. Individual 5 × 7 cm gene-corrected grafts denoted by a letter and delineated by blue dots and lines. A One graft was placed on a small wound on subject 2’s back. Investigator global assessment showed 50–74% wound healing compared to baseline at year one, and ≥ 75% healing at years four and five. B One graft applied to a small wound on subject 2’s chest demonstrated ≥ 75% healing through year four, 50–74% at year five, and ≥ 75% from year six onwards. C Four adjacent grafts were placed on subject 7’s upper back. ≥ 75% healing was sustained through year five. D Six contiguous grafts were applied to large, confluent wounds on subject 6’s back. From year one, all showed 50–74% or < 50% healing, likely due to early graft loss

Fig. 3

Patient-reported presence of any pain or itch at chronic RDEB wounds before and after treatment. Summary of presence of (A) pain (binary option: yes/no) and (B) itch (binary option: yes/no) at chronic, open RDEB wounds before and after treatment with 5 × 7 cm gene-corrected autologous keratinocyte grafts

Fig. 4

Patient-reported pain and itch at treated chronic RDEB wounds, stratified by wound healing. Summary of treated chronic RDEB wounds with (A) pain (binary option: yes/no) and (B) itch (binary option: yes/no), stratified by wounds demonstrating < 50% wound healing and ≥ 50% wound healing as determined by investigator global assessment (IGA). Statistically significant differences in pain and itch by graft site healing were estimated by Fisher’s exact test