Genetic Complexity Behind EB Simplex Slows Gene Therapy Progress

Karen McGuire, PhD, chief executive officer and co-founder of BioMendics, spoke with Dermatology Times from the debra Care Conference in Los Angeles, California, about the genetic factors limiting gene therapy development for epidermolysis bullosa simplex (EBS). McGuire outlined how EBS differs biologically from dystrophic and junctional EB, and described renewed patient engagement at this year's conference.

Genetic Differences Between EB Simplex and Other EB Subtypes

Early gene therapies targeted conditions with clearer biological mechanisms, McGuire said. Recessive dystrophic EB involves a biallelic mutation in the COL7A1 gene, leaving patients with little to no functional collagen in the dermis. Replacing the missing protein became a defined goal for early gene therapy programs.

EB simplex presents a more complex picture, McGuire noted. Patients carry autosomal dominant mutations in keratin 5 or keratin 14, with mutation locations varying widely within the alleles. Other genes, including PLEC and KLHL, are also associated with the condition.

"We say simplex is not simple. There's nothing simple about it, including the genes," McGuire said.

How Keratin Mutations Weaken Skin Structure

EB simplex patients are not missing the keratin protein, McGuire explained. Instead, they produce both a normal and a pathologic version of the protein simultaneously. The result is a mix of functional and mutated keratin within basal keratinocytes.

This mix weakens the intermediate filament networks, the major structural proteins in basal keratinocytes, and forms the basis for recurrent blistering.

"The advances in dystrophic EB have been incredibly important for changing the overall landscape of how we view EB therapies," McGuire said.

Patients Drifting Away From Dermatologic Care

Many people living with EB simplex learn to manage the condition largely on their own, McGuire said. Families build routines around wound care and footwear, and over time many stop seeing a dermatologist after concluding no new treatment options exist. Disease severity is more pronounced in pediatric patients than in adults, she added.

"I think there's a lot of dermatologists out there that probably have more patients with EBS in their communities than they realize," McGuire said.

She noted patients not actively connected to a dermatologist or to organizations such as debra of America are harder to reach with information on clinical trials and emerging therapies.

Renewed Engagement at the debra Cares Conference

This year's debra Care Conference drew significantly more interest and engagement from the EB simplex community than in prior years, McGuire said. More than 50 families attended EB simplex-focused sessions, a turnout she described as notable for a rare disease community.

"There were more sessions focused on EBS this year than ever before, we had over 50 families in attendance, which is an amazing number for a rare disease community," McGuire said.

Her message to patients and clinicians is to reconnect, given how quickly the science is moving. Staying connected to a dermatologist and to the EB community helps ensure patients do not miss opportunities to learn about new research and future treatment options, she said.