Spray-on-Skin

About This Project

Study of the Safety, Tolerability, and Efficacy of an iPS Cell-based Therapy for Recessive Dystrophic Epidermolysis Bullosa Delivered with a Spray on Skin Device

Lay summary

Induced pluripotent stem (iPS) cells are a type of stem cell generated from other adult cells. Like other stem cells they can become another type of cell in the body. Patient iPS cells can be gene-corrected and then returned to the patient to treat EB. Following on from earlier work in the EB iPS Consortium, this early-phase clinical trial will evaluate the safety and efficacy of transplanting the gene-corrected cells into up to five Recessive Dystrophic Epidermolysis Bullosa (RDEB) patients using a novel Spray-on-Skin device, as a potentially more straightforward and cost-effective alternative to skin grafts.

Scientific Summary

RDEB is caused by mutations in COL7A1, leading to absence or deficiency of functional collagen VII (Col7), an integral component in the adhesion of epithelia to dermis in the skin and mucous membranes. Remission from the open wounds of RDEB could be obtained if functional Col7 is replaced in the skin. However, a durable remission can only be attained if an affected patient’s cells are genetically corrected, and a sufficient number of renewable cells engraft back into wounds. This pilot, phase 1 study will evaluate the safety and efficacy of one such approach in patients with RDEB who have the common mutation c.7485+5G>A. Using an ex vivo approach, the patient’s skin cells will be genetically corrected and reprogrammed into induced pluripotent stem cells (iPSCs) in an efficient one step process. The iPSCs will be differentiated into functional keratinocytes and fibroblasts expressing Col7. These keratinocytes and fibroblasts will be transplanted to the patient using a novel Spray-on-Skin device developed by AVITA Medical.

The primary objective of this study is to evaluate the safety of this treatment approach. After treatment, patients will be monitored for 1 year for the development of squamous cell carcinoma or teratomas within the treated areas, immune reactions, and other adverse events. The secondary objectives are to provide proof-of concept data that the use of genetically corrected iPSC-derived keratinocytes and fibroblasts will function normally and are an effective treatment for chronic wounds in patients with RDEB. The expression of Col7 and formation of anchoring fibrils after treatment will be evaluated. In addition, wound closure and the durability of wound closure compared to standard wound care will be studied. We hypothesize that this treatment will be safe and well-tolerated and lead to the regeneration of histologically normal skin expressing Col7 that is not prone to re-wounding. If successful, this work will lay the foundation for the development of iPSC-based therapies for other monogenic diseases affecting internal organs, where the difficulty in monitoring adverse effects of an iPSC-based therapy would make them unlikely first targets.

Project update December 2024

While promising, this iPSC-based therapy is still in the early stages and requires significant research before testing in humans. In the U.S., to start a clinical trial, researchers must submit a formal application called an Investigative New Drug (IND) application to the FDA. This process begins with an INTERACT meeting with the FDA for early guidance, followed by a pre-IND meeting to finalize necessary safety studies.

Over the past year, we have accomplished several important milestones toward starting a clinical trial for RDEB:

First, we have developed a way to make genetically corrected iPSC-derived skin cells under strict manufacturing standards (cGMP), which is required for an approval for a clinical trial. Using skin mini-organs called organoids, we now generate both types of skin cells needed – keratinocytes and fibroblasts – in a single process from iPSCs. These organoid-derived cells are more consistent and functional than the cells generated with earlier methods, reducing manufacturing costs and simplifying production. Our local cGMP facility has successfully completed three production runs, confirming the reliability of our process.
Second, we have modified the method for delivering our genetically corrected iPSC-derived skin cells to patients, with valuable support from our clinical partner, Dr. Anna Bruckner, and her team. Initially, we planned to use a “Spray-on-Skin” device to apply skin cells on to patients. However, we have transitioned to a new method that is both simpler and gentler on the cell product. This approach involves mixing the cells into a fibrin gel and delivering them to RDEB wounds using a dual-chamber syringe. In our studies, we found that frozen, genetically corrected skin cells can be thawed and applied effectively. These frozen cells could be stored and easily transported from a manufacturing site to any hospital for application, increasing the accessibility of our therapy to a wider range of RDEB patients. Based on this approach, our revised cell product for the clinical trial will consist of frozen, genetically corrected RDEB iPSC-derived keratinocytes and fibroblasts. These cells will be thawed and mixed with fibrin gel immediately prior to being delivered to the patient.
Third, using funding from this project and others, we tested the persistence of iPSC-derived cells in mice. The cells could stay on the animals for 3-8 months without causing tumors, demonstrating both safety and long-term effectiveness of our therapy.

Finally, we are combining all our data into a formal INTERACT document for the FDA, which we plan to submit in the first quarter of 2025. This submission represents a major step forward in bringing our therapy to clinical trials and ultimately to patients. Our progress would not have been possible without the support of our funding partners.

Researchers