Study of gene therapy by "exon skipping" for intronic mutations in the pre-clinical phase
A large international research group named "Exon skipping, Intron 11" emerged to try to solve the diagnosis and promote research on finding a cure for a type of mutation that, until relatively recently, was impossible to detect by sequencing the genome: Intronic Mutations. An intron is a nucleotide sequence within a gene that is excised by RNA splicing during the maturation of the final RNA product. Introns do not code for a protein sequence, but they are essential for the regulation of gene expression.
In order to detect this type of mutations, the research group used an approach called transcriptome sequencing. This technique focuses on the transcribed message, rather than the original DNA sequence and, therefore, allows for the detection of changes in the level of gene transcription. Their research found a profoundly intronic mutation that causes a severe form of muscular Collagen VI –related dystrophy, which displays subtle symptoms at birth, delayed walking and a later rapid progression to Ullrich-Congenital Muscular Dystrophy (UCMD).
This intronic mutation, found specifically in the ColVIA1 gene, creates a new splice site that activates the insertion of a pseudoexon, which in turn results in the inclusion of an additional 24-amino-acid sequence into the ColVIa1 protein. This additional abnormal segment of the protein negatively interferes with its correct function and leads to the observed pathogenic effects.
The encouraging news about this particular class of mutations is that they are susceptible to correction by a gene therapy approach known as "exon skipping".
An international research team from the National Institute of Health (NIH) of the United States, led by Dr Carsten Bonemann, and University College London, led by Professor Francesco Muntoni, has already obtained positive results using a similar approach of "exon skipping" in isolated cells from UCMD patients displaying such intronic mutation. In these cells, the researchers managed to suppress the inclusion of the pseudoexon during transcription, thus restoring the resulting RNA message and its protein product to its original form and function.
This same team is developing a mouse model carrying the intronic mutation that clinically displays this type of congenital muscular dystrophy, along with a genetic patch capable of correcting the mutation. This strategy may then be translated into a treatment for patients with this type of mutation.
The researchers will test the exon-skipping strategy in the new UCMD mouse model. This involves injecting the mice with synthetic strands of DNA called molecular patches, which instruct the collagen- VI producing cells to ignore or 'skip' the additional exon in the COL6A1 gene. This aims to restore collagen VI protein production in the mice and stabilize, or at least slow down, the progression of the disease.
The financial requirements of this initial phase are covered until August 2019 by MDUK (Muscular Distrophy UK.)
This initial phase of the project, which encompasses proof-of-concept studies, is being financed by MDUK:
See news from Muscular Distrophy UK.
Financing objective of the Noelia Foundation:
Our objective, in collaboration with the US patient organization Cure CMD, and our commitment with the group of scientists developing this potential therapy, is to obtain the necessary funds to conduct the next and crucial phase: advancing from the "proof of concept" into a pre-clinical study that, if successful, would precede clinical trials in patients.
COLLECTED UNTIL JULY 31, 2020: 55.815,52 EUROS.