Translating stem cell therapies for EBS into the clinic (Roop 4/Vlinderkindje)

Short lay summary

No effective treatments are available for epidermolysis bullosa simplex (EBS). Advances in reprogramming adult cells into immature cells, called induced pluripotent stem cells (iPSCs), may allow for the development of a permanent treatment option for EBS. In a clinical scenario, skin cells can be biopsied from an EBS patient and then “reprogrammed” into iPSCs. These iPSCs can be grown outside the body, genetically corrected and differentiated into new skin cells, which in turn can be administered back to the same patient. The generation of iPSCs from the same patient in need of treatment would not only potentially avoid the complication of immune rejection, but also provide an unlimited and scalable source of patient-specific cells suitable for transplantation. Given its novelty and unconfirmed therapeutic efficacy, an iPSC-based therapy will require extensive pre-clinical research before it can be approved for a clinical trial by US and European regulatory agencies. In the US, the approval of a clinical trial requires a specific application, called an investigative new drug (IND) application, to be filed with the US Food and Drug Administration (FDA). This proposal will generate IND-enabling safety, potency and efficacy data for our iPSC-based therapy for EBS and will allow us to submit a pre-IND application with the FDA.

Scientific summary

For the generation of safety and efficacy data, we will focus on a cohort of patients suffering from the Dowling-Meara subtype of EBS (EBS-DM). Given the possibility of delayed wound healing in EBS patients, which can compromise the engraftment of genetically corrected iPSC-derived skin cells, we will assess the efficacy of systemically delivered mesenchymal stem cells (MSCs) to improve the engraftment of iPSC-derived skin cells. These systemically delivered MSCs may also promote healing of lesions in the oral mucosa and gastrointestinal track, which may occasionally exist in EBS patients. MSCs are already being tested in clinical trials for many other conditions such as myocardial infarction, stroke, meniscus injury, limb ischemia, graft-vs.-host disease and autoimmune disorders. If successful, the systemic delivery of MSCs will improve the outcomes of the iPSC-based therapy that we are currently developing for EBS and may allow for faster recovery of EBS patients post-transplantation.

Strategic relevance

We will generate required safety and efficacy data for an iPSC-based therapy for EBS to obtain approval for a clinical trial. The next step will require successful outcomes of the therapy in the actual clinical trial.

The approach offers a permanent treatment option for patients with EBS-DM. The potential risks of the therapy may include tumor formation due to the incomplete differentiation of iPSC into skin cells. However, this problem can be avoided if strict quality control tests are followed. These tests will be developed during the course of this study and the safety of the therapy will be validated.

Unlike other treatments which only provide temporary relief for EB patients, this study offers the possibility of developing a permanent cure for EBS.