Background

Motor neuron disease (MND) is a devastating and rapidly-progressive orphan disease which leads to paralysis and death usually within five years from diagnosis. There are currently no therapies which slow or stop the accumulation of debilitating symptoms resulting from the underlying neurodegeneration. In the UK at any one time around 5,000 people are living with MND; 55,000 people have MND across France, Spain, Italy, the UK, USA, Japan and Germany. There are around three new cases of MND per 100,000 people, per year.

Frontotemporal dementia (FTD) is the second most-common form of early-onset dementia. It manifests as profound personality abnormalities and is debilitating for sufferers and their families. There are approximately four new cases per 100,000 people, per year.

These two diseases have in common mutations in a gene called C9ORF72. > 10% cases of MND/FTD have C9orf72 expansion mutations. 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).

RuvBL1/2 are proteins with a cellular role in clearing aggregated proteins and manipulating DNA. They interact with the protein product of a gene called MATR3 which is associated with MND. Because of the MATR3 connection and because it is known that DNA damage and protein aggregates are a feature of MND, the researcher team wanted to see if RuvBL1/2 levels are changed in cells from patients with MND and if manipulation of RuvBL1/2 levels could ameliorate the disease phenotype.

Technology Overview

Researchers have shown that overexpression of RuvBL1/2 decreases DNA damage markers and the expression of C9ORF72‑related DPRs. They have generated AAV vector constructs that express RuvBL1 or RuvBL2 and are currently planning to test these in mice with C9ORF72 mutations.

Benefits

The only approved treatment for MND in Europe and the US is riluzole but it offers at best a small increase in survival time for patients. There is a gap for a significantly better disease‑modifying treatment for MND. AAV RuvBL1/2 gene therapy promises to provide disease modification from a single dose.

Applications

The gene therapy vectors encoding RuvBL1/2 could be used as a treatment for the 10% of MND patients and FTD patients that have the C9ORF72 mutation. Furthermore, increased activity of RuvBL1/2 could also treat more‑common protein aggregation diseases including Alzheimer’s disease and Parkinson’s disease.

Opportunity

Looking for investors, collaborative development partners and funders to help us continue the RuvBL1/2 gene therapy programme.

RuvBL1/2 Gene Therapy for Motor Neurone Disease and Frontotemporal Dementia

Patents

IP Status

Seeking