New ALS disease drivers identified in genetically defined patient subgroups
Paving the way for more personalized diagnosis and effective treatments
Key findings
- First genetic evidence for targets modulated by existing therapies indicated for ALS/MND and its symptoms
- 32 therapeutic targets linked to specific patient subgroups, including RBFOX1, which has been implicated in several biological mechanisms believed to underlie ALS pathology
- Accompanying genetic biomarker sets to identify more effective therapeutic strategies and match them to the patient subgroups that are most likely to demonstrate benefit
- Biomarkers to enable the design of precision medicine clinical trials for ALS treatments with higher probability of success
- Potential to reduce biomarkers to practice in the form of a simple non-invasive test that identifies the mechanistic cause of a patient’s disease and their most effective treatments
PrecisionLife Identifies New Disease Drivers and Therapeutic Targets in ALS Through AI-Driven Mechanistic Patient Stratification
Amyotrophic lateral sclerosis (ALS) is a complex disease with a strong genetic component. However, many of the ALS disease-causing genetic factors remain elusive, reflecting the high degree of heterogeneity among patients and the existence of distinct patient subgroups with different causes and molecular mechanisms.
The Urgent Need for New Treatments
Currently there are only three approved therapies for the treatment of ALS, Riluzole, Edaravone and Tofersen. These drugs have either very limited clinical benefits or only address a small proportion of the sporadic patient population. Thus, there is an urgent need to develop new treatments, specifically for sporadic ALS. This is, however, hampered by high clinical trial failure rate attributed to highly heterogenous population and lack of specific biomarkers.
Identification of Potential Drivers and Therapeutic Targets
The PrecisionLife combinatorial analytics and AI platform has generated uniquely detailed insights into the underlying biology of ALS, stratifying patient populations and uncovering their disease-causing mechanisms.
Our analysis revealed a series of potential drivers and therapeutic targets in ALS, with varying degrees of novelty and prior evidence linking them to the disease. Interestingly, our studies found the first genetic evidence for targets modulated by existing therapies indicated for MND and its symptoms, such as riluzole, retigabine and baclofen.
RBFOX1: A Novel Therapeutic Target in ALS
PrecisionLife has identified 32 new therapeutic target candidates for ALS, including the sporadic disease. Among these, we report RBFOX1, an RNA-binding protein implicated in alternative splicing. RBFOX1 has not been previously associated with ALS but has existing links to key processes involved in the disease.
Genetic Biomarkers for Patient Stratification & Clinical Trial Design
PrecisionLife drug targets are supported by genetic biomarkers (mechanistic patient stratification biomarkers or PSBs) relevant to mechanistic etiologies present in specific subgroups of patients.
Patient stratification biomarkers link patient subgroups to drug targets, clinical trials, and treatments by the underlying mechanisms of their disease. These biomarkers will enable the design of precision medicine clinical trials for ALS treatments with higher probability of success by enabling the recruitment of patients who are most likely to respond positively to the candidate treatment.
Mechanostics®: Non-Invasive Genotypic Testing
Our biomarkers can also be used in clinical practice in the form of a non-invasive saliva-based genotypic test (Mechanostics®). Mechanostic tests provide a simple means for clinicians to identify the mechanistic cause of a patient’s disease and those patients most likely to benefit from an approved treatment.
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