Targeting Pathologic TDP-43 as a Therapeutic Approach in C9orf72 Disease
Abstract
Mutations in the C9ORF72 gene were recently identified as the most frequent cause of the devastating neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This gene contains a short sequence, which is normally repeated between 2 and 30 times in healthy individuals. This repeated sequence is abnormally expended hundreds to thousands of times in patients with disease-causing C9ORF72 mutations. These disease expansions give rise to atypical protein species that accumulate in neurons, which progressively malfunction and die. In addition, sick neurons of C9ORF72 patients are filled with protein "clumps" (also called aggregates) consisting of a protein named TDP-43, which is pathologically altered in the vast majority of ALS and FTD patients. How these TDP-43 protein aggregates form and why they harm neurons remains unknown, but their formation is directly linked to neuronal dysfunction and death in these diseases. Importantly, these toxic aggregates seem to transfer from cell to cell within a patient s nervous system, thereby spreading their toxicity to more neurons as the disease progresses. Here, we propose to test whether a novel class of human-derived antibodies that specifically recognize such disease-associated proteins can confer a therapeutic benefit by triggering their clearance and preventing their spreading in two complementary experimental mouse models of C9ORF72 disease. Moreover, using cutting-edge technologies, we have created fully human in vitro models, which will be used to mechanistically investigate the effect of selected human antibodies in TDP-43 aggregate-dependent neurotoxicity. This project represents a synergistic collaboration between academic investigators and an innovative biotechnology company. Neurimmune has developed a unique platform to identify human antibodies against misfolded proteins implicated in neurodegenerative diseases. While most immunotherapy approaches rely on humanized mouse monoclonal antibodies, Neurimmune has discovered that antibodies against misfolded proteins linked to diseases are occasionally produced in healthy individuals. Neurimmune has developed a method to isolate such antibodies by screening the blood of a large cohort of elderly healthy individuals and has successfully applied this technology to a wide spectrum of targets in neurodegenerative diseases including TDP-43. The resulting recombinant human monoclonal antibodies are highly effective and safe, due to their unique binding properties and selectivity towards pathological forms of human proteins (also called autoantigens). The use of antibodies as therapeutic agents, a strategy also called immunotherapy, instigated major breakthroughs in the cure of cancers and encouraging results were recently reported in Alzheimer s disease. Indeed, Aducanumab, an antibody against beta-amyloid identified by Neurimmune is currently tested in Alzheimer s disease patients in a clinical trial led by Biogen Idec with extremely encouraging interim results. Here, we propose, for the first time, to evaluate the therapeutic potential of immunotherapy in the most common genetic cause of ALS. Considering the predominance of TDP-43 pathology in most instances of ALS/FTD, including C9ORF72 carriers, we propose to determine whether this innovative immunotherapy approach may induce the clearance of pathogenic species accumulating in disease. This synergistic collaboration between academic investigators and a biotechnology company has the potential to uncover new insights on the toxicity of TDP-43, especially in the context of C9 RF72 mutations, and to establish the preclinical proof of concept for a novel immunotherapy for ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810092
Entities
People
- Clotilde Lagier-tourenne
Organizations
- Massachusetts General Hospital
- United States Army