Crucible Therapeutics

Background

ALS is a neurodegenerative disease that causes the progressive loss of motor nerves leading to progressive paralysis and death usually within 2-5 years from symptom onset (peaking at 60-65 years old). FTD involves the degeneration of frontal and temporal lobes of the brain causing altered personality features and death within 8-10 years from symptom onset (40-65 years old).

Hexanucleotide repeat expansions in the C9ORF72 gene are the most common known genetic cause of ALS (responsible for 10% of cases) and FTD (responsible for 5% of cases). These repeat expansions result in complex mechanisms of neuronal injury including the production of dipeptide repeat proteins (DPRs) which have a variety of toxic effects and constitute one of the main drivers of disease.

There are ∼5,500 ALS and ∼10,000 FTD patients living with C9ORF72-linked diseases across the USA, EU and Japan. The two licensed ALS treatments, riluzole and edaravone, have only a modest effect on life expectancy (2-3 months) while patients remain paralysed.

There are ∼1,500 and ∼2,000 new ALS and FTD cases per year respectively but there is no cure available.

Technology overview

Crucible Therapeutics is developing gene therapy vectors to treat C9ORF72-linked ALS and FTD. 

These therapies work by altering the functioning of the protein, Serine/arginine-rich splicing factor 1 (SRSF1), which is responsible for the nuclear export of pathological C9ORF72-repeat transcripts and the subsequent production of DPRs. Reduced production of DPRs results in reduced neurotoxicity and neuronal loss. CGT-01, the lead gene therapy vector, lowers the amount of the SRSF1 protein in the central nervous system while CGT-02 and CGT-03 allow expression of SRSF1 inhibitors.

Stage of development

The team have shown that reducing the expression of SRSF1 confers neuroprotection in vitro in motor nerves derived from C9ORF72-ALS patients and in vivo in a fruit fly model of C9ORF72-ALS/FTD. In vivo proof of principle data also show safety and efficacy of the lead gene therapy vector (CGT-01) in C9ORF72-ALS/FTD mice including the reduction of toxic DPRs. The safety and efficacy of CGT-02 and CGT-03 are currently being evaluated in vivo in C9ORF72-ALS/FTD mice.

Envisaged timeline for commercialisation of CGT-01:

Funding

£2.2m - 2016-2024

Motor Neurone Disease Association (2016-17)

Medical Research Council New Investigator (2017-21)

MRC and MND Association grants (2016-2021) funded the discovery phase of the research by identifying the mechanism of action of SRSF1 depletion and its neuroprotective potential as a therapeutic strategy in C9ORF72-ALS/FTD cell and fly models.

Biotechnology and Biological Sciences Research Council (2018-23)

LifeArc/MND Association (2021-24; CGT-01 proof-of-principle)

The LifeArc grant financed from the Philanthropic fund and co-funded by the MND Association (2020-2024) is focused on the development of the gene therapy approach and its proof-of-principle efficacy and safety in a mouse model of C9ORF72-ALS/FTD.

Cell and Gene Therapy Catapult Commercialisation of Research (2022-2023)

Patents

This technology has been granted EU and US patents.

Team

Founding partners:

Supported by:

Dr Jon Field, Knowledge Exchange and Commercialisation Manager Sheffield Healthcare Gateway, Faculty of Medicine, Dentistry and Health at the University of Sheffield

Cell and Gene Therapy Catapult