The research conducted by the Translational Neurobiology of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Laboratory led by Tania Gendron, Ph.D., focuses on deciphering the molecular causes of, and identifying biomarkers for, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and other neurological disorders with the ultimate goal of expediting the discovery of effective treatments for these diseases. Using patient biofluids and brain tissues along with preclinical models, Dr. Gendron seeks to uncover protein markers that will facilitate the earlier diagnosis of ALS and FTD, better estimate disease prognosis, aid in the screening of therapeutic candidates, and confirm target engagement of potential therapies in clinical trials.
- Molecular mechanisms of ALS and FTD. A common feature of many neurodegenerative diseases is the pathological accumulation of protein aggregates. Dr. Gendron and her team study the role of aggregation-prone proteins — such as TDP-43 and tau — in ALS, FTD and related disorders. Recently, she and her Mayo Clinic colleagues discovered a novel neuropathological hallmark of ALS and FTD caused by a hexanucleotide repeat expansion in the C9orf72 gene: Dipeptide repeat (DPR) proteins are atypically produced from the expanded repeat. Investigating how these DPR proteins contribute to C9orf72-associated ALS and FTD (c9ALS/FTD) is a key interest of her laboratory.
- Biomarker discovery. Given the clear need for biomarkers for ALS, FTD and other neurodegenerative diseases, Dr. Gendron's laboratory pairs mechanistic investigations with translational studies. Through such studies, poly(GP) DPR proteins were established as a promising pharmacodynamic biomarker of repeat-targeting therapeutics for c9ALS/FTD and spinocerebellar ataxia 36, and neurofilament proteins were demonstrated to be strong predictors of prognosis for ALS, FTD and all major stroke types. Ongoing studies seek to identify panels of biomarkers to expedite the earlier diagnosis of neurological disorders and improve the estimation of prognosis.
Significance to patient care
For numerous neurodegenerative diseases, no effective treatment exists. Among the reasons for this is the lack of biomarkers. For example, many clinical trials for neurodegenerative diseases are believed to have been hampered because treatment was initiated too late in the disease course. Biomarkers that facilitate the earlier diagnosis of neurological disorders would aid in overcoming this barrier. Pharmacodynamic biomarkers also are needed to confirm that the drug being tested in clinical trials does indeed have the intended biological effect.
Finally, an additional challenge of clinical trials is the variability of disease severity among patients, which makes it difficult to determine whether the drug being tested has an appreciable effect. Prognostic biomarkers that allow patients to be stratified into more uniform groups would ameliorate the difficulties in detecting beneficial treatment outcomes. By addressing these challenges, Dr. Gendron's laboratory endeavors to improve clinical trial design, patient care and treatment development.