The Dawn of Topical Gene Editing: Epithelica’s Approach to Skin Disease
A new era in dermatology is unfolding, one where genetic diseases of the skin could be treated not with lifelong creams and bandages, but with a targeted, potentially curative gene editing approach. Epithelica, led by CEO Gaurav Sadhnani, is pioneering this field, focusing on in situ gene correction delivered via lipid nanoparticles (LNPs) and laser microablation. The company’s work, recently detailed in a published study, represents a significant step toward realizing the promise of gene editing for a wide range of skin conditions.
Addressing the Challenge of Skin Delivery
Delivering gene editing tools to the skin has historically been a major hurdle. The skin’s natural barrier function, the stratum corneum, effectively blocks biomacromolecules from reaching the living cells below. Epithelica’s solution – utilizing short pulses from a commercially available dermatological laser to create temporary, microscopic pores – offers a clinically viable pathway. These pores allow LNPs carrying the gene editing machinery to penetrate the skin, with the pores closing again within 16 hours.
“The procedure can be performed with commercially available lasers, which many dermatology centres are equipped with,” explains Sadhnani. “Dermatologists are already very familiar with laser-assisted skin treatments, so from a practical perspective, this fits naturally into existing clinical workflows.”
Focusing on Autosomal Recessive Congenital Ichthyosis (ARCI)
Epithelica’s initial focus is on autosomal recessive congenital ichthyosis (ARCI), a group of rare inherited conditions causing severely dry, scaling skin. Current treatments are palliative, often costing families upwards of $35,000 annually and carrying significant side effects. The company is employing a cytosine base editor (eTd-CBE) to correct a common mutation in the TGM1 gene, responsible for a significant proportion of ARCI cases.
The study demonstrated up to 26% on-target editing in patient-derived keratinocytes, with no detectable editing of nearby ‘bystander’ bases – a crucial safety feature. In vivo toxicity studies in mice showed no significant adverse effects, even with repeated dosing.
Gene Editing Rates and Clinical Significance
Even as gene editing rates in 3D skin models reached approximately 12% (with some samples reaching 24%), translating these numbers to clinical benefit is key. Sadhnani emphasizes that the threshold for success isn’t a specific molecular number, but rather visible, meaningful improvement for patients. Studies in other genodermatoses suggest that restoring as little as 5-10% of normal protein levels can alleviate severe symptoms.
The team achieved roughly 3% restoration of normal TG1 enzyme activity in their models, placing Epithelica’s results within a clinically relevant range.
Durability: The Remaining Question
A critical unanswered question is the durability of the gene editing effect. Sarah Hedtrich, Epithelica’s academic co-founder at the University of British Columbia, highlights the need to determine whether the treatment edits the skin’s stem cell populations, ensuring long-term correction through natural epidermal turnover.
“The central open question is durability – specifically, whether we are editing the stem cell populations that sustain long-term tissue renewal,” Hedtrich states. However, she adds that even limited durability could represent a substantial improvement over existing treatments.
Beyond ARCI: A Platform for Genodermatoses
Epithelica’s technology has the potential to address a vast landscape of genetic skin diseases. The company estimates that its platform could be applicable to approximately 500 known genodermatoses, with different guide RNAs and base editors tailored to specific mutations. No other company has yet reported in situ base editing directly in human skin using a topical LNP approach.
The company has filed a patent covering its core platform and holds Orphan Drug Designation from both the FDA and EMA for ARCI, accelerating the regulatory pathway.
Navigating the Regulatory Landscape
Epithelica is positioning its therapy within existing regulatory frameworks for advanced therapy medicinal products. Sadhnani believes the FDA’s proposed Plausible Mechanism Pathway, which allows for approval based on mechanistic plausibility and early clinical benefit, could be a viable route to market.
Funding and Future Directions
Epithelica is currently raising a seed round to fund GMP manufacturing and prepare for first-in-human trials. A successful rescue in a human patient is seen as a major value inflection point. The company plans to remain focused on ARCI initially, establishing a strong foundation before expanding into other indications.
Frequently Asked Questions
Q: What is autosomal recessive congenital ichthyosis (ARCI)?
A: ARCI is a group of rare genetic skin disorders causing severely dry, scaling skin across the entire body.
Q: How does Epithelica’s approach differ from existing treatments?
A: Current treatments for ARCI are palliative, focusing on symptom management. Epithelica aims to correct the underlying genetic defect, potentially offering a cure.
Q: What role does the laser play in the treatment?
A: The laser creates microscopic pores in the skin, allowing the gene editing tools to reach the target cells.
Q: What is the biggest challenge facing Epithelica?
A: Determining the durability of the gene editing effect – whether the correction lasts long-term – is the primary remaining challenge.
Q: Is this approach safe?
A: Preclinical studies in mice have shown no significant adverse effects, and the team has demonstrated minimal off-target editing.
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