Lentiviral-mediated COL7A1 gene-modified cell therapy for recessive dystrophic epidermolysis bullosa (Qasim 1)

Short lay summary

New treatments for EB are becoming feasible as technologies are developed to add new genes to defective cells. Certain viruses can permanently add a corrected copy of the collagen gene to cells. We will use a disabled virus to infect skin fibroblast cells collected from people with recessive dystrophic EB and grow them in the laboratory. After introducing the corrected gene, the cells will be injected into skin, where we expect they will produce new collagen protein and prevent blisters. This proposal is asking for support to make enough virus to show the approach works and to treat around six people with recessive dystrophic EB in the first instance. If successful, the same virus could be used to modify other cell types, including bone marrow stem cells, which could provide benefit for the whole body.

New treatments for EB are desperately needed. Certain viruses can permanently add a corrected copy of the collagen gene to cells, and the treatment called “gene therapy”. We have used a disabled virus as an agent to infect skin cells collected from people with recessive dystrophic EB and grew them in the laboratory. To address above challenge, we explored gene therapy for RDEB. We know that in RDEB there are inherited mutations in the COL7A1 gene which lead to a lack of the type VII collagen (C7) protein in the skin.

Scientific summary

Being able to restore C7 in RDEB skin by gene therapy would lead to fewer blisters and stronger skin. Funding from DEBRA has facilitated to develop gene therapy as a means of restoring C7 in RDEB skin. We carried out laboratory research to correct some RDEB cells from the RDEB patients. We made an artificial copy of the COL7A1 gene and used a safe, non-toxic virus as an agent to deliver the new COL7A1 gene into RDEB patient skin cells called, fibroblasts. These treated cells are called “gene-corrected fibroblasts” and can produce perfect C7. The fibroblasts are cells which are normally found in the dermis of the skin and which can make collagens and other proteins that keep skin healthy. Viral delivery systems are commonly used as an agent, in gene therapy work because they can efficiently transfer the replacement gene to where the defective gene resides and thus compensate for the genetic problem. Once they deliver the desired gene, the viruses are self-inactivated so that they do not cause other diseases. We have established protocol to correct the skin cells and make new C7 in RDEB patient fibroblasts and then carried out the essential intensive safety checks on the viral agent and also conducted an animal experiment to test the correction of skin. We have established the protocols to produce high quality gene therapy product in good manufacturing practice labs (highly clean labs, suitable to produce gene therapy products without any organisms to give to RDEB individuals), so that we could then use this product in people suffering from RDEB. The work has been completed and now we have started a safety and efficacy assessment, called clinical trials of this new treatment to use in humans with RDEB.

Strategic relevance

No effective treatments are available for recessive dystrophic epidermolysis bullosa (RDEB). 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 RDEB. Specifically, skin cells can be biopsied from a RDEB 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 biggest hurdles in advancing an iPSC-based therapy into the clinic are the low efficiency of gene correction and the large number of steps in developing this therapy. To reduce the complexity of an iPSC-based therapy, we have combined genetic editing of RDEB skin cells and their reprogramming into iPSCs into a one-step procedure. In this project, we will improve the efficiency of genetic correction of RDEB mutations in our simultaneous gene editing/reprogramming approach. We will also adapt our simultaneous gene editing/reprogramming approach to cells derived from urine specimens to provide an alternative non-invasive source of somatic cells for RDEB
therapy. If successful, this study will accelerate the clinical translation of an iPSC-based therapy for RDEB and other forms of EB.