Sebastian Michels, MD, on the Role of Alternative Polyadenylation in ALS Disease Pathogenesis
The postdoctoral fellow and member of the La Spada Lab at University of California, Irvine, discussed findings he presented at ANA’s 2023 conference that may have implications for future RNA therapy development.
“Our research doesn't only apply to ALS, but is potentially relevant for all TDP-43 proteinopathies, such as frontotemporal dementia or Alzheimer disease. We are trying to identify key APA transcripts that are relevant for these diseases to then construct oligonucleotides that sterically block a poly(A) signal to reverse these phenomena.”
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which treatment options are limited and restricted mainly to slowing disease progression. Although the cause of ALS is still not well understood, some research has suggested that abnormalities in RNA metabolism caused by the displacement of the nuclear protein TDP-43, which is involved in the regulation of RNA expression, into the cytoplasm, may be a factor in disease pathogenesis.
In order to investigate this further, Sebastian Michels, MD, a postdoctoral fellow and member of the La Spada Lab at University of California, Irvine, and his colleagues evaluated alternative polyadenylation (APA), a mechanism that plays a role in RNA processing and is regulated by TDP-43, and how changes in APA affect RNA expression. Michels presented their findings in a talk entitled “Alternative polyadenylation in the pathogenesis of amyotrophic lateral sclerosis” at the 148th Annual Meeting of the American Neurological Association, held September 9-12, 2023, in Philadelphia, Pennsylvania.
In an interview with CGTLive™ at the conference, Michels gave an overview of the current state of ALS treatment and research and discussed the key results he presented at the conference, along with their implications for the healthcare community. He noted that ALS research as a whole is currently focused on 2 main areas: seeking biomarkers that could allow for earlier diagnosis, and thus earlier enrollment in clinical trials for experimental treatments; and seeking a better understanding of the disease pathology in order to inform the development of new treatments. In terms of his team’s own research, which falls into the latter category, Michels highlighted that they identified hundreds of changes in genes that function in pathways that have been previously implicated as playing a role in ALS. Michels also spoke about the potential to use key APA transcripts identified by this type of research in the development of targeted oligonucleotides that could treat ALS and other similar diseases.
Click here for more coverage of ANA 2023.
REFERENCE
Michels S. Alternative polyadenylation in the pathogenesis of amyotrophic lateral sclerosis. Presented at the 148th Annual Meeting of the American Neurological Association, held September 9-12, 2023, in Philadelphia, Pennsylvania.
Considerations for Administering Hemoglobinopathy Gene Therapies From a Pharmacist’s Perspective
April 20th 2024Alexis Kuhn, PharmD, BCOP, a pediatric oncology pharmacist at Mayo Clinic, discussed the incorporation of the recently FDA-approved gene therapies for SCD and TDT into the work of pharmacists.
