In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial
A non-viral and selection-free COL7A1 HDR approach with improved safety profile for dystrophic epidermolysis bullosa
29 May 2021
Stanford Adult Epidermolysis Bullosa Anesthesia Protocol 
5 September 2022

Nat Med. 2022 Apr;28(4):780-788. doi: 10.1038/s41591-022-01737-y. Epub 2022 Mar 28. PMID: 35347281; PMCID: PMC9018416.

In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial

Authors: Irina Gurevich 1Pooja Agarwal 2PeiPei Zhang 2John A Dolorito 1Stacie Oliver 2Henry Liu 2Nicholas Reitze 2Nikhil Sarma 2Isin Sinem Bagci 1Kunju Sridhar 1Visesha Kakarla 1Vamsi K Yenamandra 1Mark O’Malley 2Marco Prisco 3Sara F Tufa 4Douglas R Keene 4Andrew P South 3Suma M Krishnan 2M Peter Marinkovich 5 6

Affiliation:

  1. Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  2. Krystal Biotech, Pittsburgh, PA, USA.
  3. Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
  4. Microscopy Unit, Shriners Hospital for Children, Portland, OR, USA.
  5. Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. mpm@stanford.edu.
  6. Veterans Affairs Medical Center, Palo Alto, Stanford, CA, USA. mpm@stanford.edu.

Abstract:

Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain-severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

Download: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018416/