October 20, 2023

Dr. Laura Ranum, PhD
Kitzman Family Professor of Molecular Genetics and Microbiology
Director, Center for NeuroGenetics, College of Medicine, University of Florida

Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that affects nerve cells in the brain and spinal cord that control muscle movement. Over time, patients lose muscle control. The disease typically affects people between 40 and 70 years old. Currently, there are no effective treatment strategies for ALS.

In 2011, scientists identified the C9orf72 gene as the most common cause of familial and sporadic ALS. This gene underwent a novel process called repeat associated non-AUG (RAN) translation. This process led to the production of multiple variations of toxic proteins (RAN proteins). RAN translation of the C9orf72 mutation in the brain and spinal cord of ALS patients produces toxic proteins that form clumps that contribute to the disease pathology.¹ Understanding how to stop, or even slow, the production of these toxic proteins could impact disease outcomes and patient well-being.

According to Dr. Laura Ranum and her team at the University of Florida, the popular diabetes drug, Metformin, could be repurposed as a viable therapeutic option for ALS patients. Metformin is an FDA approved, widely prescribed, and well-tolerated type 2 diabetes drug recently shown to reduce the production of toxic proteins.² In fiscal year 2018 (FY18), Ranum received an ALS Research Program (ALSRP) Therapeutic Development Award to investigate the therapeutic potential of Metformin to treat ALS patients with the C9orf72 repeat expansion (C9-ALS). Then, in FY21, Ranum received an ALSRP Therapeutic Idea Award with a Biomarker Option for follow-up work to identify new genes and target novel RAN proteins found in some cases of sporadic ALS.

Ranum’s team hypothesized that Metformin could reduce RAN protein levels by preventing specific enzymatic activity (i.e., protein kinase R activity) which drives the processes facilitating toxic protein production. They demonstrated neurons from C9-ALS mice and C9-ALS patient brains have elevated levels of activated protein kinase R compared to unaffected controls. The team also showed that Metformin treatment reduced protein levels in cells and a mouse model of C9-ALS and improved behavior and disease progression in the mice. The results show that RAN proteins are major drivers of disease for ALS, and targeting RAN proteins for reduction, via Metformin, improves disease presentation in mice.

Ranum’s team also realized that the levels of RAN proteins in patient-derived cells and organoids could act as biomarkers, or potentially identifiable signs, to determine if someone has ALS and/or is successfully responding to treatment. Interestingly, additional work by Ranum’s team showed RAN proteins may be relevant for ALS patients, and for patients with some genetically unknown forms of sporadic ALS.

Overall, the identification of an already FDA-approved drug and an understanding of how it works in a preclinical animal model is a major step forward in the search for viable ALS therapeutics. This work directly led to an initial clinical trial in a small group of C9-ALS patients (ClinicalTrials.gov Identifier: NCT04220021). In FY22, Ranum’s lab received further support from the ALSRP for a Pilot Clinical Trial Award (PCTA) to support completion of this human phase 2 clinical trial. The clinical trial is being performed at the University of Florida as a collaborative effort between Ranum; Dr. James Wymer, Professor and Division Chief of Neuromuscular Neurology; Dr. Emily Plowman, Professor of Speech, Language, and Hearing Sciences; Dr. David Vaillancourt, Professor and Chair of the Department of Applied Physiology and Kinesiology; and Dr. Timothy Garrett, Associate Professor of Pathology.

In addition to assessing Metformin as a treatment for C9-ALS, Ranum’s FY22 PCTA also supports continuing to identify biomarkers. The team collectively intends to assess biomarkers to detect disease onset and progression, along with determining if toxic RAN proteins are major causes of ALS. The success of the ongoing clinical trial with Metformin could help disease outcomes and connect patients with an effective, already approved, therapeutic.

References:

¹Zu, T., Gibbens, B., Doty, N. S., Gomes-Pereira, M., Huguet, A., Stone, M. D., Margolis, J., Peterson, M., Markowski, T. W., Ingram, M. A., Nan, Z., Forster, C., Low, W. C., Schoser, B., Somia, N. V., Clark, H. B., Schmechel, S., Bitterman, P. B., Gourdon, G., Swanson, M. S., Moseley, M., and Ranum, L. P. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108, 260-265.

²Zu, T., Guo, S., Bardhi, O., Ryskamp, D. A., Li, J., Khoramian Tusi, S., Engelbrecht, A., Klippel, K., Chakrabarty, P., Nguyen, L., Golde, T. E., Sonenberg, N., & Ranum, L. P. W. (2020). Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proceedings of the National Academy of Sciences of the United States of America, 117(31), 18591–18599.

Links:

Public and Technical Abstracts: Therapeutic Potential of Metformin, an FDA-Approved Drug, and PKR Targeting for C9orf72 ALS

Public and Technical Abstracts: Identifying and Targeting Novel Repeat-Associated Non-AUG (RAN) Proteins in Sporadic ALS

Public and Technical Abstracts: Safety of Metformin in C9orf72 ALS: Effects on RAN Proteins, Breathing, Imaging, and Metabolomic Outcome Measures

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