Topical gene therapy for recessive dystrophic epidermolysis bullosa

Medicom Medical Publishers spoke with Prof. Peter Marinkovich (Stanford University, CA, USA) about the US Food and Drug Administration (FDA) approval of beremagene geperpavec (B-VEC) for patients with dystrophic epidermolysis bullosa (DEB), a rare and severe skin condition. We learn a little bit about this condition, and how Prof. Marinkovich’s team has developed an effective gene therapy that has shown very promising results in their clinical trial, published recently in the journal Nature Medicine [1]. 

Dr Marinkovich was a primary investigator in the multi-centre, randomised, double-blind, placebo-controlled GEM-3 trial. The phase 3 trial had met both its primary and secondary endpoints, with B-BEC-treated patients having a substantially greater rate of achieving complete wound healing from DEB than placebo at 3 and 6 months (P <0.005) [1]. Before the PDUFA date’s announcement, trial data on 31 DEB patients indicated that around 70% of wounds had closed within 6 months of treatment, including the patient that had the dominant form of DEB. Medicom spoke with Dr Marinkovich to gain more insights.

What do physicians need to know about DEB?

“Dystrophic Epidermolysis Bullosa (DEB) is a rare and challenging genetic disorder that falls under the broader spectrum of epidermolysis bullosa (EB). This inherited condition is characterised by a heightened susceptibility to skin blistering, particularly in response to minimal trauma or friction. DEB results from mutations in the COL7A1 gene, impairing the production of type VII collagen, a crucial component of the basement membrane within the skin. The hallmark feature of DEB is the formation of recurrent blisters beneath the epidermis, leading to chronic wounds, scarring, and, in severe cases, significant disability. The impact extends beyond the skin, affecting mucosal surfaces, the eyes, and internal organs, amplifying the complexity of its management.”
“As healthcare professionals, understanding DEB is essential for timely diagnosis and comprehensive care planning. The evolving landscape of gene therapies and innovative treatments brings hope for improved outcomes, making it imperative for medical practitioners to stay abreast of the latest advancements in the field. This introduction aims to provide a foundational understanding of DEB, fostering increased awareness and facilitating more informed and empathetic care for patients with this challenging dermatologic condition.”

Given the complexity of DEB, what are the current therapeutic approaches available for patients?

“Currently, supportive care is the mainstay of DEB management. This includes wound dressings to minimise trauma during dressing changes, nutritional support, and infection control. However, there's a critical need for treatments addressing the root cause of the disease, particularly the collagen deficiency. Innovative approaches, such as gene therapy, have shown promise in addressing this deficiency and are currently undergoing clinical trials.”

Your work has been instrumental in exploring gene therapy for DEB. Could you elaborate on how gene therapy works in the context of this disorder?

“Certainly, gene therapy involves introducing a functional copy of the defective gene into the patient's cells to correct the underlying genetic mutation. In the case of DEB, where the COL7A1 gene is mutated, gene therapy aims to restore the production of functional type VII collagen. This can be achieved through different methods, such as skin grafting or topical applications, providing a targeted and potentially transformative approach to treating DEB.”

What are some of the challenges and successes you've encountered in the development of gene therapy for DEB?

“One challenge has been addressing the immune response to viral vectors used in gene therapy. However, our recent use of an HSV1-based vector has shown promise in evading the immune system, minimising adverse events, and allowing for repeat applications. We've seen success in clinical trials, with some patients experiencing significant improvements, marking a significant stride in the pursuit of effective DEB treatments.”

Looking ahead, what developments or areas of research do you find most promising for advancing DEB treatment?

“I'm particularly excited about expanding gene therapy applications to mucosal tissues, eyes, and other affected areas in DEB patients. Additionally, the recent approval of a topical gene therapy offers a more accessible and convenient treatment option, potentially transforming how patients receive care. Exploring these avenues holds great promise for improving the quality of life for individuals living with DEB.”

Reference

1. Gurevich I, et al. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat Med. 2022 Apr;28(4):780-788.

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Posted on 17 November 202323 November 2023