An abnormality in the human genetic system known as a repeat expansion that is located in a certain genetic location identified as C9orf72, is the most common cause of both inherited (transmitted between family members) and sporadic (no known family history) forms of amyotrophic lateral sclerosis and frontotemporal dementia (C9 ALS/FTD). There are currently no effective treatments available for C9 ALS/FTD, or for the more than 50 other diseases that share this type of genetic abnormality. In the brain and spinal cord of many patients with these repeat expansion mutations, a recently identified process called repeat associated non-AUG (RAN) translation has been shown to cause the production of toxic proteins (RAN proteins) and the accumulation of these proteins as aggregates that contribute to the disease. Metformin is a widely used, well-tolerated type-2 diabetes drug that was recently shown to block an important process that allows formation of toxic RAN protein aggregates in the brain. In a mouse model of C9 ALS/FTD, metformin treatment decrease RAN protein aggregates in the brain and improved the behavior of the mice. These data suggest metformin may also benefit patients C9 ALS/FTD. The purpose of this project is to complete a small-scale research study in human patients to test the safety and possible effectiveness of metformin for the treatment of C9 ALS and if the drug shows promise, to prepare for a large multi-site placebo-controlled follow-up trial.

This study will (1) determine the safety of using metformin for the treatment of C9-ALS/FTD;

(2) test if metformin reduces the RAN protein levels in patient body fluids; (3) identify substances in body fluids that can help to diagnose the disease earlier and track disease progression more effectively, and (4) if the current project is successful, a larger study will compare how different people respond to the use of this medication and whether it can improve their condition. This study has the possibility of rapidly moving this well-tolerated U.S. Food and Drug Administration (FDA)-approved drug into the clinic as a safe, low-cost treatment for the most common genetic cause of both ALS and FTD. Due to metformin’s very strong safety profile, RAN protein lowering potential and strong anti-inflammatory properties, the time and work that it takes to complete most drug studies may be significantly shortened. This may allow faster FDA approval for use of metformin in C9 ALS patients. Importantly, if successful, metformin would be a very inexpensive treatment for C9orf72 ALS patients. Given that toxic (RAN) protein build up has also been identified in other repeat expansion diseases, results from this study may be able to help people with other diseases as well.

This study will be important to this area of science because it will go beyond finding out whether metformin can help in C9 ALS patients. We also collect a lot of other important information from other tests that will be performed during the trial, which will help in future studies of this kind. For example, despite a lot of progress in understanding C9-ALS, very little is known about the hidden systems that cause the disease, and that affect patients and their quality of life. The scientific testing of other data collected in this study from procedures like MRIs, breathing and swallowing studies, and repeated collection of body fluids (blood, etc.) will help identify new information to focus on in future studies. The resulting information will be useful in planning and assessing if drugs for future trials of ALS, FTD, and other neurological diseases are working. All of these results will allow physicians and scientists to have better and easier ways to watch over patients affected by this disease by means of blood test results and more that will not only improve clinical trial design and outcomes, but will also have a positive impact on patient care, treatment, quality of life, and management of ALS.