Background

Expansion of a hexanucleotide repeat G4C2 in the non-coding region of chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause for motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS). 10% of ALS cases harbour a C9orf72 mutation. C9orf72 mutation is also the leading genetic cause of frontotemporal dementia (FTD).

Growing evidence suggests that C9orf72 repeat expansions also contribute to a wide spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, multiple sclerosis, Parkinson’s disease and cerebellar ataxias.

While non-pathogenic C9orf72 alleles possess between 2 to 25 repeats, pathogenic repeat expansions vary from tens to thousands. C9orf72 expansions are bidirectionally transcribed leading to the formation of intracellular sense and antisense RNA repeat expansion (RRE) foci. Moreover, the transcripts are prone to repeat-associated non-ATG (RAN) translation producing dipeptide repeat proteins (DPRs). The etiology of C9orf72-linked ALS/FTD is currently not clear, although several causal mechanisms have been proposed: disease arising from a loss of function, which is supported by a reduction in C9orf72 transcripts in patients with RREs; a toxic gain of function induced by the sequestration of RNA-binding proteins resulting in the formation of RRE foci and DPRs.

Technology Overview

With the advent of CRISPR/Cas9 gene editing technology, targeted mutations of a specific gene region through the generation of insertion/deletions (indels) which ultimately disrupt the gene function have become an attractive method for therapeutic interventions. Researchers at The University of Sheffield have designed and tested a self-complementary adeno-associated virus serotype 9 (scAAV9)-mediated CRISPR/Cas9 gene editing approach for targeting guide RNA molecules to the genomic sequences located immediately outside the C9ORF72 expansion region. The results from using the approach on C9‑ALS patient-derived cells in culture and in mice with the C9ORF72 expansion suggest that this approach has therapeutic validity.

Benefits

Treats the cause of C9orf72‑ALS/FTD. Targets only the mutant allele. Potentially, a single dose would be disease‑modifying.

Applications

There are around 55,000 prevalent ALS patients in US, UK, Spain, Germany, Italy, France and Japan combined. Of these, around 5,500 would be directly suitable for this therapy. Furthermore, the FTD market would be larger and there is potentially scope to use this therapy in more‑common diseases where C9orf72 mutation may be a contributing factor, including Alzheimer’s, Huntington’s, multiple sclerosis, Parkinson’s and cerebellar ataxias.

Opportunity

Seeking development partners, funding and investment to continue the development of this gene therapy programme

CRISPR-Cas9 Gene Therapy for Motor Neurone Disease with C9ORF72 Mutations

IP Status

Seeking