An Exosome Vaccine Approach for the Prevention and Treatment of C9orf72 ALS/FTD
Abstract
Background: Microsatellite repeat expansions or short sequences of genetic code that are repeated too many times cause more than 50 human diseases. The most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is caused by a repeat expansion mutation in a gene located on chromosome 9 called the chromosome 9 open reading frame 72 (C9orf72) gene. ALS is a devastating disease that results in the death of motor neurons in the brain and spinal cord, which leads to paralysis and death. In addition to ALS, mutations in this gene can also cause frontotemporal dementia, a disease that can cause apathy, loss of emotional control, and cognitive decline. Some patients with the C9orf72 mutation develop ALS, others develop frontotemporal dementia, and some develop both. These diseases are referred to as C9-ALS/FTD. Despite a significant amount of research, there are no effective treatments for ALS, FTD, or any of the more than 50 other microsatellite expansion disorders. The Ranum lab recently demonstrated that an antibody-based therapy that targets and destroys an unexpected type of protein that is produced by the C9orf72 mutation increases lifespan, improves behavior, and prevents motor neuron loss in a C9-ALS/FTD mouse model. These unexpected proteins are called repeat associated non-AUG (RAN) proteins, and this study showed that targeting RAN proteins is a promising therapeutic strategy for C9-ALS/FTD. Because antibodies are very expensive to produce, we propose to develop a vaccine that will allow people that have the C9orf72 mutation to produce their own anti-RAN protein antibodies to fight the disease. Codiak BioSciences is a leader in developing therapeutic exosomes, including for vaccine applications. Exosomes are very small, nano-sized vesicles produced by cells that can interact with other cells in the body and alter the biology of recipient cells. Codiak BioSciences has harnessed the ability to engineer exosomes to alter the immune system, including to elicit the production of helpful antibodies. In this application we provide strong proof-of-concept data that immune therapy can improve disease in C9-BAC mice. We will now test the hypothesis that exosome-based vaccines that target C9-mutant RAN proteins can be used to fight C9-ALS/FTD. Scientific Objective: The objective of this proposal is to develop an exosome-based vaccine that will allow patients to produce antibodies that will fight C9-ALS/FTD by targeting and removing harmful RAN proteins from cells in the brain and spinal cord. Clinical Application and Patient Impact: A vaccine therapy is likely to be useful for treating both symptomatic C9-ALS/FTD patients and for preventing disease in asymptomatic C9orf72 gene carriers. Given that RAN proteins are found in more than 50 repeat expansion disorders, a similar vaccine strategy may be applicable other repeat expansion disorders. Time for Patient-Related Outcomes: Preclinical data generated by this project will identify exosome-based vaccine candidates for the treatment of C9-ALS/FTD, which will pave the way for future clinical trial patients. Codiak BioSciences expertise in vaccine design and production and the Ranum group s expertise in C9-ALS/FTD and testing therapeutic approaches coupled with the biomarkers that will be developed in this application should make it possible to fast-track vaccine candidates into early-stage clinical trials in a relatively short period of time. Contribution to Therapeutic Development: This project has the potential to advance to the clinic an innovative, cost-effective, and safe treatment option for symptomatic C9-ALS/FTD patients and asymptomatic gene carriers that advances beyond any currently available or in-development treatments. Given that RAN proteins are found in a growing number of expansion diseases, data generated in this project has potential applications for a large group of other neurological diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110515
Entities
People
- Timothy Soos
Organizations
- United States Army