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A Disruptive, Non‐Viral Gene Editing Platform Technology for Treating Genetic Conditions

Completed
Project leadProf. Wenxin Wang
Organisation Charles Institute of Dermatology, School of Medicine, University College Dublin
Project budgetEUR 217,070.00
Start date / Duration01. Jan 2019 / 12 months
Funder(s) / Co-Funder(s) Others
Other funder(s)Science Foundation Ireland- Future Innovator Award
Research area Molecular therapy, Cellular therapy

Project details

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.

Scientific summary

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.

Strategic relevance

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.

What did this project achieve?

This project is still ongoing, however to date there has been significant progress in developing our proposed non-viral gene editing therapy for RDEB. Provisional in-vitro results have been very promising and initial in vivo assessments have given cause for optimism. Using our non-viral gene editing approach, we have successfully demonstrated the targeted deletion and subsequent correction of COL7A1 after a single transfection in both cell lines and primary cells. COL7A1 correction after multiple topical applications has been achieved in a humanized EB mouse model, validating the feasibility of our approach. As RDEB is both an internal and external fragility disorder, affecting organs including the eyes, we sought to and have successfully demonstrated the correction of COL7A1 in corneal cells as well as lung cells in-vivo after nasal administration. Furthermore, as our non-viral delivery system can be used to carry “genetic scissors” targeted to alternative genomic locations, the platform applicability of our approach cannot be underrated. Through modifying these genomic targets our platform technology could be adapted to other mutations in RDEB as well as other EB subtypes, giving great cause for optimism for our approach. Finally, a number of hurdles and barriers were identified in relation to clinically translating this therapeutic approach, and subsequently successfully overcome resulting in us further improving our therapeutic delivery system. During the course of this project, substantial research progress has been made in the development of our non-viral gene editing therapeutic and we are optimistic that with continued support this exciting therapeutic approach will be successfully developed for the treatment of patients with RDEB.


Keywords

Wang
gene therapy
RDEB
Gene Editing
CRISPR-Cas9
Non-Viral Delivery
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