Senotherapy for ALS
Abstract
Evidence is emerging that brain senescence associated with progressive brain inflammation is one of the mechanisms underpinning neurodegenerative diseases, including ALS. Hallmarks of brain senescence are present in ALS models and patient post-mortem tissues. Although there remains a gap in knowledge between the observations of brain senescence and its direct causative role in neurodegeneration, harnessing the therapeutic potential of targeting senescence to stop disease progression could address the urgent clinical need for treatments. Indeed, it was recently demonstrated that this approach could attenuate the cognitive decline seen in an Alzheimer s preclinical model. In C9orf72 linked to ALS/FTD, the extent and contribution to the disease of senescence have not yet been tested. We propose to characterize and validate a C9orf72 ALS/FTD cell-based model in which we can study the basic biology of senescence. Several therapeutic strategies, known as senotherapies, have been developed to eliminate tissue-specific cells undergoing senescence or senescent cells. However, almost none have been tested in models of ALS. Senescent cells provide ideal targets for cell-based immunotherapy (a.k.a. CAR-T cell immunotherapy). CAR-T cell immunotherapy was first applied for cancer. Several CAR-T cell immunotherapies are now approved by the U.S. Food and Drug Administration for different types of cancer, and several are being tested in clinical trials. We will build upon our expertise in CAR-T cell design and cancer applications to directly measure the ability of this approach to clear senescent cells for C9orf72-ALS/FTD therapy, in combination with IFNgamma and IL-6 inhibitors to preserve CAR-T cell efficacy while suppressing the potential cytokines side effects. Several small molecules have already been identified to exhibit anti-senescence activity, but most lack potency and produce substantial side effects. Here, we try the therapeutic concept that CAR-T cells targeting senescent cells can be an effective anti-senescence therapy. CAR-T cell research has advanced rapidly in the clinic for different types of cancer. It is back to the bench, with trial results informing new mechanisms of efficacy, toxicity, and resistance and catalyzing the search for new targets and application of novel technologies. Innovation in CAR-T design and methodologies are bound to lead to improved responses and transform the treatment of patients, potentially including patients with neurodegenerative conditions. Should this study provide promising results, we will seek to advance the CAR-T cell therapeutic approach to different pre-clinical models of ALS and C9orf72 ALS/FTD. This project is focused on a fast-to-patient development program. After developing a preclinical proof of concept, a CAR-T cell product will be advanced into a subsequent Phase I clinical trial in patients with C9orf72-ALS/FTD, with objectives establishing that this new approach is safe and well-tolerated. Validation of the CAR-T cell anti-senescence therapeutic approach could be extended to other forms of ALS, including sporadic ALS, as a next step of this project. Proceeding directly to clinical testing in ALS patients is also appropriate. CAR-T cell approaches have already been tested for different brain cancers, including certain lymphomas of the central nervous system. The Weinberg ALS Center, in which this study will be conducted, is also an appointed member site for NEALS, a nation-wide consortium for centralized ALS clinical trials, whose member sites are medical institutions equipped and set up to perform large ALS clinical trials. This arrangement will allow for a rapid translation of scientific advances from this project into clinical research and new treatments for people with ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310258
Entities
People
- Davide Trotti
Organizations
- Thomas Jefferson University
- United States Army