A Disruptive, Non‐Viral Gene Editing Platform Technology for Treating Genetic ConditionsCompleted
|Prof Wenxin Wang
|Charles Institute of Dermatology, School of Medicine, University College Dublin, IRELAND
|Start date / Duration
|01. Jan 2019 / 12 months
|Funder(s) / Co-Funder(s)
|Science Foundation Ireland- Future Innovator Award
|Molecular therapy, Cellular therapy
Short lay summary
RDEB is one of the most severe subtypes of EB and arises due to mutations in the Collagen VII structural protein. To date, RDEB has no clinical therapy beyond palliative care and therefore, a therapy to restore the structural integrity of skin directly to the patients’ own cells is greatly required. Our approach is to use the latest gene editing technology to treat the source of the disorder, namely mutations in Collagen VII. For this, we will deliver a targeted “genetic scissors” to cut out mutations in Collagen VII, using our specialized biomaterial carrier systems. The aim of this project is the development of a non-viral gene editing treatment that can be applied topically to the skin in a non-invasive manner to correct patients mutations and restore structural integrity to the skin. It has been demonstrated that the successful delivery of this “genetic scissors” to cells by our biomaterial delivery agent has restored the function Collagen VII after topical applications to cells and animal models.
The skin is an accessible organ making it ideally suited for topical application based therapeutics. RDEB is an inherited skin fragility disorder with no current treatments beyond palliative care. Our proposed solution is the development of a gene editing therapeutic for the curative treatment of RDEB. This solution consists of two state of the art components, namely a synthetic biomaterial for delivering genetic cargo to cells and a CRISPR gene editing component to correct mutations and restore integrity to the skin. The proposed strategy involves the use of a CRISPR-Cas9 system to employ a targeted genomic deletion at intronic sites flanking prominent mutations in COL7A1, resulting in a restoration of the reading frame lacking pathogenic mutations. Our therapeutic will be applied topically onto RDEB patients’ wounds to correct disease mutations in a non-invasive manner thereby circumventing painful and invasive procedures including, biopsies surgeries and safety concerns related to immunogenicity associated with the use of viral based delivery systems. For patients currently suffering with RDEB this treatment will vastly improve quality of life and reduction in pain, whilst for new-borns our solution will act as a disease preventative measure. Our preliminary results have demonstrated the therapeutic potential of our non-viral gene editing approach both in-vitro and in-vivo. Moreover, great strides have been taken to address scalability and manufacturing of our therapeutic, to fully realise the clinical translatability for RDEB patients.
Our proposed solution is a gene editing therapy that can be applied topically to patients skin enabling in vivo correction of patients cells by “cutting out” mutations in Collagen VII, thereby restoring its functionality. Successful completion of project goals will demonstrate the feasibility of using a non-viral gene editing therapeutic approach in vitro and in vivo to correct and restore functionality to Collagen VII and thus structural integrity to RDEB skin. The culmination of this work will also assess the clinical up-scaling and production of this therapeutic molecule for clinical application. Following completion of this project, the next steps would be a full pre-clinical phase toxicity and efficacy assessment.