Understanding ALS Disease Biology to Pursue Repair and Regeneration
The Impact of Gene Fusions on ALS Disease Progression: Ghazaleh Sadri-Vakili, MD, PhD
Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS) and over 50 causative or
disease-modifying genes have been identified and linked to the disease. Additionally, genetic risk factors
also contribute to sporadic ALS; however, the causes of more than 80% of cases are still unknown. One
major potential genetic cause of ALS may be structural variants, such as deletions, duplications,
insertions, inversions and translocations within the genome that had not been systematically examined.
We recently used publicly available RNA-Seq datasets from Target ALS and the ALS Consortium and
deployed an open-access software to identify any possible gene fusion events in ALS.
Our analysis revealed there is a significant increase in fusion genes in ALS and identified 90 rare gene
fusion pairs in ALS, defined as those absent from control cases as well as from known cancer databases,
given that fusion events are well-characterized in cancer. Since the causes of more than 80% of ALS cases
are still unknown, the identification of ALS-specific gene fusions may improve our understanding of the
mechanisms underlying motor neuron loss and identify novel potential therapeutic targets.
Additionally, there is an urgent unmet need of biomarkers for both ALS diagnosis and prognosis. In this
respect, ALS-specific gene fusions may be a viable diagnostic biomarker and, once we characterize their
molecular consequences, they may also serve as potential prognostic biomarker. We predict that
ALS-specific gene fusions may improve many aspects of clinical care as already demonstrated in the field
of oncology and are now working to understand how the fusions effect ALS disease progression.
Ghazaleh Sadri-Vakili, MS, PhD directs the NeuroEpigenetics laboratory at
MassGeneral Institute for Neurodegenerative Disease, where she focuses on
identifying common mechanisms that cause neurodegenerative disease to
identify novel therapeutic targets. In ALS, the laboratory is assessing the
pathogenic role of neuroinflammation, oxidative stress and the epigenome.
Together with colleagues from the NCRI, the Sadri-Vakili lab uses biofluids to
identify new diagnostic and prognostic biomarkers of disease. In addition, Dr.
Sadri-Vakili works closely with partners in industry and routinely tests the
therapeutic effects of novel small molecules and FDA-approved compounds in
animal models of ALS.
