Anti-RAN Targeting Immunotherapy for C9orf72 ALS and Genetically Unknown RAN-Positive Sporadic ALS
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a complex set of neurological diseases that kills motor neurons and results in a devastating loss of motor function and death. Approximately 90% of ALS cases do not have a family history of the disease and are referred to as having sporadic ALS (sALS). The lack of knowledge of the underlying causes of sALS presents a huge barrier to finding effective therapies. The most common genetic cause of sALS is too many copies, referred to as an expansion, of a GGGGCC sequence in a gene located on chromosome 9 called the chromosome 9 open reading frame 72 (C9orf72) or C9-ALS. In 2011, the Ranum lab made the surprising discovery that these repeat expansions produce unexpected toxic repetitive proteins without the normal signals previously thought to be required for cells in the body to produce proteins. These repetitive proteins are called repeat-associated non-AUG (RAN) proteins because they are made without the normal AUG protein start signal. RAN proteins have been shown to be toxic to cells and to play an important role in C9-ALS. Treating mice with antibodies against the C9 RAN proteins improve the disease features in mice that mimic the disease (C9-BAC mice). While this approach is promising, it is costly, requires frequent injections, and does not penetrate the brain, which justifies the need for a second-generation antibody approach that targets RAN proteins. Patient Population: This anti-RAN antibody approach is primarily targeted at ALS patients with the C90orf72 mutation. However, the Ranum lab has recently shown that these RAN proteins also accumulate in a large number of sALS autopsy brains that are curiously negative for C9 and SCA36. This data suggests this anti-RAN antibody approach may also be effective in the much larger group of sALS cases. This proposal will test if this antibody approach works with both C9-ALS mice and sALS cells, which will ultimately lead to potentially providing a therapeutic option for large portion of the existing ALS population. Research and Clinical Application: The ultimate application of this research is the generation of a therapeutic treatment for ALS patients in addition to increasing our knowledge about how ALS develops and how RAN proteins contribute to the disease. In the future this research will provide supporting evidence for potential future clinical trials that will determine how effective the approach will be for reducing symptoms in ALS patient. The benefits of this approach will be that it targets the cause of the disease, RAN proteins, at a molecular level rather than the symptoms of the disease. Additionally in the case of sALS patients, this approach does not require knowledge of the disease-causing mutation just simply the fact that the patient s cells express a RAN protein that already has an antibody against it. The risk of this approach is that it requires expression of the antibody using a viral vector, which can cause inflammation, although this virus approach is already used in a number of existing therapies. Since the underlying genetic mutation for the sALS cell models used in this proposal has not been identified nor have animal models generated, this avenue of research will not progress at the same rate as the C9- based work. However, the demonstration that this AAV-alpha-GA immunotherapy approach works in a large portion of sALS cases will provide strong impetus for future clinical trials. Time for Patient-Related Outcomes: The current research application is in the preclinical stage and could provide, at least for C9-ALS, efficacy data in support of a future clinical trial in the 2-5 year post-study time frame. While the AAV-based approach to face more regulatory hurdles than already approved Food and Drug Administration drugs, such as metformin, there are over 250+ current clinical trials on clinicaltrial.gov that utilize AAV. By the end of the proposed study, if sufficient precl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310287
Entities
People
- Laura Ranum
Organizations
- United States Army
- University of Florida