Development of immunotherapy targeting pathological TDP-43 in ALS and FTLD - Amyotrophic lateral sclerosis (ALS), a disease in which premature loss of upper and lower motor neurons leads
to fatal paralysis, is increasingly recognized to have clinical, genetic and pathological overlap with frontotemporal
lobar degeneration (FTLD), a neurodegenerative disorder characterized by behavioral and language
dysfunction. In 2006, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of
ubiquitinated cytoplasmic inclusions observed in both ALS and FTLD patients and dominant mutations in the
gene TARDBP were subsequently identified as a primary cause of ALS. ALS is the most common motor neuron
disease in adults and FTLD the most common dementia under the age of 60. Nevertheless, there are no effective
therapies for these neurodegenerative disorders and management focuses on treating the symptoms and
providing palliative care in order to improve the quality of life of these patients.
Immunotherapies against neurodegenerative diseases are still at their early stages of development. Yet, we
believe that they hold tremendous potential due to their direct impact on the underlying disease biology and their
potential to delay disease progression. Naturally occurring human monoclonal antibodies represent novel
therapeutic molecules for neurologic disorders including ALS. It is postulated that human autoantibodies
targeting misfolded pathogenic proteins, such as TDP-43, serve as surveillance molecules to eliminate toxic
aggregates before they can elicit a deleterious response. Such antibodies might neutralize the activity of
oligomers and/or facilitate clearance of deposited aggregates via microglia uptake. Chimeric or humanized
antibodies can elicit an adverse immune response, resulting in severe side-effects, even death, and reduced
efficacy of the therapeutic antibody due to neutralization by the human immune system. Autoantibodies retrieved
from individuals with no debilitating conditions have a higher safety profile, as the antibody has proven tolerability
in the human body. Combined with the outstanding affinity maturation typical of the human immune system,
those antibodies are likely to offer a therapeutic window superior to antibodies of non-human origin.
A bottleneck in the development of effective therapies against ALS and FTLD is the lack of models with
pathological features faithfully resembling those present in patient brains. Our recent work has established new
cellular models of TDP-43 aggregation, via the introduction of pathological forms extracted directly from patient
brains, leading to accumulation and propagation of pathology in cell lines and human neurons via a mechanism
mimicking the molecular events leading to disease progression. In this project, we will capitalize on these
tools to develop TDP-43 immunotherapy. Our strategy is to identify patients with naturally occurring
protective autoantibodies targeting pathological forms of TDP-43 and to proceed with their respective
cloning, characterization and development for therapeutic use in ALS and FTLD.
