This is a guest post by Nadia Houri, a Business Development Analyst with the Centre for Commercialization of Regenerative Medicine (CCRM).
In October 2015, I attended the Till & McCulloch Meetings (TMM) in Toronto, of which my employer, CCRM, was a co-organizer. Dr. Michele De Luca (Centre for Regenerative Medicine, University of Modena and Reggio Emilia) gave a presentation on the use of epithelial stem cells in two very different autologous therapies, a talk I was greatly anticipating.
Dr. De Luca and long-time collaborator Dr. Graziella Pellegrini were the driving force behind the development of Holoclar, the first advanced therapy medicinal product (ATMP) containing stem cells to be approved in Europe. Holoclar was approved by the European Medicines Agency (EMA), in February 2015, for the treatment of moderate to severe limbal stem cell deficiency (LSCD) caused by physical or chemical burns to the eye. Limbal stem cells are important for corneal regeneration and reside in the limbus, at the border between the sclera and the cornea. A deficiency in these cells leads to corneal opacity and vision loss. Holoclar consists of ex vivo expanded corneal epithelial cells, including limbal stem cells. As it is an autologous therapy, patients undergoing this treatment must have a certain amount of surviving limbus available for tissue biopsy.
After an overview of Holoclar, the remainder of Dr. De Luca’s talk focused on his and Dr. Pellegrini’s efforts to develop a therapy for epidermolysis bullosa (EB). EB is a group of inherited connective tissue diseases that cause the skin to blister and be fragile like butterfly wings, hence the term “butterfly children” when referring to younger patients. There is currently no cure for EB, only palliative treatment. Patients with severe forms of EB have a very poor quality of life, short life expectancy, and a high probability of developing aggressive, metastatic squamous cell carcinoma. You can learn more about EB, and watch a video between Pearl Jam’s Eddie Vedder and a boy with EB, here.
Dr. De Luca described a few case studies, including one of an adult patient, “Claudio,” who has junctional EB. In a Phase I/II trial initiated about a decade ago, colonies of epidermal stem cells (“holoclones”) were taken from the skin of Claudio’s palm and genetically modified to express a subunit of laminin-5, a protein that is normally part of the basement membrane (extracellular matrix under the skin), but whose assembly is defective in this patient.
Genetically corrected cultured epidermal grafts were transplanted onto Claudio’s upper legs, which were the most severely affected areas. A one-year follow-up study of this patient revealed promising results: the areas that received grafts had normal-looking skin without blisters, infections or inflammation, and there was normal synthesis and assembly of laminin-5.
Dr. De Luca also presented data from a follow-up study conducted almost seven years after Claudio’s procedure. The regenerated epidermis in the treated areas remained normal, which is remarkable considering the high turnover rate of skin and the length of time that has passed.
While this trial was underway, European regulatory rules on cell therapies changed in 2007 and it became a requirement to produce cell therapies under Good Manufacturing Practice (GMP) conditions. It took more than seven years to build and certify a GMP facility, Holostem Terapie Avanzate, which was a collaborative effort by the University of Modena and Reggio Emilia and Italian pharmaceutical company Chiesi Farmaceutici. Now that a GMP facility is available to Dr. De Luca and his colleagues, the EB clinical trials have resumed.
Ideally, EB patients would be treated with the autologous epidermal culture therapy at a young age for the following reasons: children have a smaller surface area for the grafts to cover, there is less stem cell depletion compared to adults and, most importantly, new lesions should be prevented from forming in patients as much as possible. However, enrolling children in a combined cell and gene therapy trial is not the easiest task due to regulatory reasons.
Dr. De Luca mentioned the case of a 7-year-old EB patient in Germany. This patient was in a burn unit due to loss of 60% of his skin, and was at a high risk of dying without intervention. Dr. De Luca’s group obtained approval from the German regulatory authority to treat this young patient. The first transplant procedure was done in October right before TMM. While it is probably too soon to tell if the therapy was effective in this case, I eagerly await future updates from Dr. De Luca’s group to learn about the progress these researchers are making in the treatment of this devastating disease.