Special Purpose Exit Company (SPEC)

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FUS-ALS Therapeutics

The FUS gene functions in ribonuclear complexes to control mRNA splcing and varations in this gene lead can cause Amyotrophic Lateral Sclerosis (ALS), as well as frontotemporal dementia, and hereditary essential tremor.

Genetic Medication Need:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons and the nerve cells controlling voluntary muscle movement and breathing. The four most common cause genes associated with ALS are C9orf72, SOD1, FUS, and TARDBP. However a variety of other genes are well associated with ALS, such as SCFD1, SETX, SPG11, SPTLC1, SQSTM1, TAF15, TBK1, TUBA4A, UBQLN2, UNC13A, VAPB, VCP (genereviews). Intriguing, an additional 38 genes have been implicated to be involved in ALS (ClinGen). Pathogenic Variation in FUS are a subset of Juvenile ALS and have the early onset at a median age of 21 years (PMID: 34946884). There is no cure for ALS. The FDA-approved drugs riluzole and edaravone prolong life by a few months, but they do not improve symptoms.  New medications are needed to stop progression and possibly reverse the disease.

Population Frequency:

In general, ALS occurs in about 10 per 100,000 in the US population (PMID: 35422180). The frequency of FUS ALS in juvenile populations is 200 times lower giving a frequency of about 1 per 2,000,000 persons, which makes pathogenic variations in this gene occur at a Rare Disease frequency. From this frequency, roughly 4,000 persons worldwide have pathogenic defects in FUS. Current ALS registries do not have an estimate for the numbers of FUS-positive patients, however over 60 variants in ClinVar database have pathogenic associations and about 30% are seen multiple times. Indicating that an addressable population near 100x should be readily attainable.

Currently Varsome has 396 variants which we have binned into 3 categories: Pathogenic, Benign, and Variants of uncertain Significance (VUS).  AlphaMissense predicts these existing calls are pathogenic for 61% of the VUS. AlphaMissense also predicts that for the entire protein, 64% of all possible single amino acid changes are pathogenic, yet Varsome has only documented 15.5% of these.  As a result, we can expect continued growth in achieving additional members to the patient population registry.

Rapid Assay:

FUS is a nucleoprotein. It functions in DNA and RNA metabolism and processing of mRNA transcripts. FUS has multiple interaction partners in the RNA metabolism and processing pathway. Using a STRINGdb analysis, we can see the top 10 interaction protein-protein interaction partners for FUS.

We will use the well established association with its partner RNA binding protein, HNRNPA2B1 to create a rapid assay. It is known that iPSC containing pathogenic P525L variant see close to 2x reduction in HNRNPA2B1 levels and that this deficiency can be restored by exposure to torkinib (PMID: 30937520)

Translational Assay:

Using a well-defined protocol to create cortical neurons from iPSC (PMID: 38242131), we will examine synaptic connectivity by scoring levels of neuronal puncta.  For instance, in a R514G variant of FUS, the levels of Synapsin puncta dramatically increase.  Hits found in the rapid assay will be cross validated for restoration of normal puncta staining after exposure to therapeutic candidates.

Drugs

Published leads for possible FUS-ALS treatment are torkinib, PQR309, paroxetine, promethazine, and trimipramine,  (PMID: 29358088). We will explore combination in attempt to identify synergistic drug combinations for FUS-ALS treatment.

Special Purpose Exit Company (SPEC)

Devinebio creates entities (SPECs) to develop drug assets for a specific indications. Five areas are monitored per each SPEC: population, biomarkers, leads, IP, and regulatory. A SPEC’s assets are moved through the milestones of preIND, IND, preNDA and NDA. As a drug asset progresses, it becomes de-risked and it increases in value. Once a drug asset has achieved IND-enabled status, it will have matured enough to be ready for partnering with Pharma.