Fen-Biao Gao, professor at the University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over three years to enhance understanding of pathogenic (disease-causing) mechanisms and identify new drug targets for ALS (amyotrophic lateral sclerosis).
Please describe your current research.
C9ORF72 repeat expansion is the most common genetic mutation known to cause ALS. To understand its pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from C9ORF72 patients and differentiated them into motor neurons and cortical neurons that recapitulate some key neuropathological features, such as abnormal accumulation of RNA “clumps” and production of unusual toxic proteins.
In our current work, we will continue to use C9ORF72 patients’ iPSCs-derived motor neurons as our experimental system, together with some studies in fruit flies. We will build upon a large body of preliminary results we have already obtained, such as that iPSC-derived C9ORF72 motor neurons showed an age-dependent increase in the number of detrimental damages to the genome. These studies will greatly enhance our understanding of ALS pathogenic mechanisms and may identify components in the DNA damage pathway as potential therapeutic targets.
What is your focus in the field of ALS research?
We aim to understand pathogenic mechanisms of ALS caused by the C9ORF72 repeat expansion. These studies will be informative for our understanding of other forms of ALS as well.
Why is your area of focus important?
C9ORF72 repeat expansion is the most common genetic cause of ALS and frontotemporal dementia (FTD). Thus, it is critically important to understand how the expanded repeats cause neurodegeneration, which may lead to the identification of novel therapeutic targets.
How will your research lead to treatments and cures?
Our research may lead to the identification of key proteins in the DNA damage pathway that can be used as the target for therapeutic intervention. If successful, the small molecule compounds that suppress this disease phenotype (disease characteristics) may be further developed for therapeutic purposes.
What do you feel people impacted by ALS can have the most hope about with respect to research right now?
Research in the C9ORF72 field is moving forward rapidly. We are hopeful that collective efforts from many researchers will bring effective treatment to patients with this mutation sooner rather than later.
Does your work have any potential implications for other disease fields?
The C9ORF72 mutation is unique compared with other ALS disease genes, but there are many other repeat expansion diseases, such as myotonic dystrophies. Pathogenic mechanisms uncovered in our study may be informative for these diseases as well.
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