DEBRA International newly funded research projects

DEBRA International newly funded research projects

From the call for research proposals across all four of DEBRA International’s research priorities last year, several new projects have been funded.

Our ‘All-priorities’ calls allow for proposals on topics which may explore in depth the causes and consequences of EB, which can lead to breakthrough novel concepts for the diagnosis or treatment of EB, through to early-stage clinical trials of treatments. The funded projects do indeed span this broad scope, from new ways of identifying mutations in people with clinical symptoms of EB but no known mutation, to new approaches to identify possible drugs to prevent the devastating muscular dystrophy that develops in a rare type of EB Simplex, to a new gene-editing approach for gene therapy for RDEB.

Before a grant can be offered, there is often a need for researchers to amend the proposed research or project budget following peer-review, to ensure that we fund the best-quality research and invest our funds appropriately. There can also be extensive negotiation of the terms and conditions of a specific contract, especially when there are multiple research groups, or commercial companies, involved in a project.

Two of the funded projects required revision of the proposals prior to funding. A further four were considered to need more extensive revision, and these researchers have been invited to revise their proposals in line with recommendations of reviewers – MSAP, external reviewers and the Patient Panel, as appropriate – and to resubmit them for reconsideration this Spring, or later, should they wish.

Of the 14 proposals received, three have to date been offered grant awards by DEBRA Austria:

“Implementation and clinical utility of transcriptomesequencing by RNA-seq in EB”
It is mutations in any one of a group of genes that code for skin proteins that result in the blistering and fragility of the skin and mucous membranes in EB. Identification of the mutated genes and the specific type of mutations in each individual patient is critical for proper diagnosis, and to predict the likely course and severity of the disease as early as possible in childhood. Knowing the specific mutation of an individual is also essential when considering suitability for treatment with some of the new, potentially curative therapies that target specific types of mutations. However, current methods of mutation detection are only partially (80%) effective, and many people with EB do not know their mutations. This project will use new technical approaches to identify new mutations, and their specific symptomatic consequences.

“Identification of novel therapeutic targets for the treatment of patients with EBS-MD”
EB Simplex associated with Muscular Dystrophy (EBS-MD) is characterized by generalized skin blistering associated with late onset muscular dystrophy, and caused by mutations in the gene encoding the protein plectin (PLEC1). Currently, there is no effective therapy or cure for EBS-MD. The aim of this project is to identify small molecules that might be useful for the treatment of EBS-MD. Such molecules allow the mutation in the plectin gene to be ‘skipped’ over, so that a smaller version of plectin protein is produced. The researchers have recently shown that this smaller plectin protein is fully functional in genetically modified mice that lack the full-length plectin. The project will carry out high-throughput screening of ‘libraries’ of  small molecules in the hope of  identifying ones that can be tested as treatments for EBS-MD patients.

“Designer nucleases-based NHEJ-mediated gene editing for the correction of a highly recurrent COL7A1 mutation in recessive dystrophic epidermolysis bullosa epidermal stem cells”
Patients with RDEB lack in their skin cells the protein Collagen VII (C7), one of the main molecular glues which keep the epidermis firmly attached to the deeper layers of tissue. The project will produce skin grafts in which the production of C7 has been restored by a technique called ‘gene editing’. These grafts should have adhesion properties similar to healthy skin and could be used for transplantation to blistered areas of skin of a patient with RDEB. The “gene edited” skin grafts would be generated using cells from the recipient patient, thus minimizing possible immune rejection problems. This therapy would be initially tailored to those who present a specific mutation in COL7A1 particularly frequent in Spanish RDEB patients, but it would be a proof of principle for the development of similar therapies for many other RDEB-causing mutations.

Dr Clare Robinson, Head of Research, DEBRA International