Epithelica’s Gene Editing Approach for Ichthyosis Advances to Clinical Trials

A new gene therapy approach offers hope for individuals living with autosomal recessive congenital ichthyosis (ARCI), a rare and debilitating genetic skin disorder. Researchers have successfully demonstrated a method to deliver gene-editing tools directly to the skin, correcting the underlying genetic mutation responsible for the condition. The work, spearheaded by a team at the University of British Columbia and now being advanced by the spin-off company Epithelica, represents a significant step forward in treating a disease for which, until now, only symptomatic relief was available.

Understanding Autosomal Recessive Congenital Ichthyosis

ARCI is a group of inherited skin disorders characterized by severely dry, scaling skin that covers the entire body. Individuals with ARCI often experience intense itching and tightness, impacting their quality of life and, in severe cases, increasing the risk of mortality in newborns. Current treatments are largely palliative, involving extensive bathing and moisturizing regimens that can be time-consuming and costly – sometimes exceeding $35,000 annually – and systemic retinoids with limiting side effects. Patients have described feeling “prisoners, locked inside their house,” highlighting the profound psychosocial impact of the condition.

Correcting the Genetic Defect

The most common cause of ARCI is a mutation in the TGM1 gene, which provides instructions for making an enzyme crucial for forming a healthy skin barrier. The research team focused on a specific, common mutation – c.877-2A>G – responsible for approximately one-third of ARCI cases. They employed a cytosine base editor (eTd-CBE) to precisely correct the mutated nucleotide back to its normal form. A key challenge was ensuring the editing occurred only at the intended site, avoiding unintended alterations to nearby DNA bases.

The team achieved up to 26% on-target editing in cells derived from patients, with no detectable “bystander” editing, a significant technical accomplishment. This level of precision is crucial for ensuring the safety and efficacy of gene-editing therapies.

Overcoming the Skin Barrier

A major hurdle in delivering gene therapies to the skin is its natural protective barrier, which prevents large molecules like gene-editing tools from reaching the living cells below the outermost layer. To overcome this, the researchers utilized a clinically approved laser microablation technique. Short pulses from a dermatological laser create microscopic pores in the skin, allowing the gene-editing components to penetrate to the target cells. These pores rapidly close within 16 hours.

According to Gaurav Sadhnani, CEO of Epithelica, the laser step is a strategic advantage. “The procedure can be performed with commercially available lasers, which many dermatology centres are equipped with,” he explains. “Dermatologists are already very familiar with laser-assisted skin treatments, so from a practical perspective, this fits naturally into existing clinical workflows.”

Safety and Delivery

The research team conducted thorough safety assessments. Studies in mice showed no adverse effects, including no deaths, changes in body weight, skin irritation, or significant immune responses, even after repeated treatments. The gene-editing components did not distribute systemically, remaining localized to the treated skin area. The lead lipid nanoparticle (LNP) formulation also showed minimal immune activation in laboratory tests.

In 3D skin models created from patient cells, the team achieved an average of 12% gene correction, with some samples reaching 24%. This translated to roughly 3% restoration of normal TG1 enzyme activity. Researchers note that even modest restoration of enzyme activity – as little as 5-10% – has been shown to alleviate severe symptoms in other genetic skin diseases, suggesting the observed levels are clinically meaningful.

The Path to Clinical Trials and Beyond

Epithelica, founded in 2025, is now focused on bringing this therapy to patients. The company is currently raising seed funding to initiate a first-in-human clinical trial and prepare for potential treatment. While acknowledging the uncertainties inherent in translating preclinical findings to humans, researchers are optimistic about the potential impact of this therapy.

Sarah Hedtrich, associate professor at the University of British Columbia and the study’s corresponding author, emphasizes the importance of durability. “The central open question is durability – specifically, whether we are editing the stem cell populations that sustain long-term tissue renewal.” However, she also notes that even a treatment requiring periodic re-administration could significantly improve the lives of patients.

The therapy is classified as an advanced therapy medicinal product under European law, and Epithelica is working within existing regulatory frameworks, leveraging Orphan Drug Designation from both the FDA and EMA to expedite the development process. The company holds a patent covering the core platform technology.

A Platform for Future Therapies?

While the initial focus is on ARCI, the researchers believe this approach could be applicable to a wide range of genetic skin disorders. Different mutations would require different gene-editing tools, but the delivery system – combining topical LNPs with laser microablation – could remain consistent. This platform approach could potentially unlock treatments for approximately 500 known genodermatoses.

The success of Epithelica’s approach hinges on securing funding and demonstrating long-term efficacy and safety in clinical trials. However, the preclinical data are promising, offering a beacon of hope for individuals and families affected by ARCI and other severe genetic skin conditions. As Sadhnani states, “The real threshold is not a molecular number. It’s whether patients and clinicians see a visible, meaningful improvement.”