Tariq Afroz (Switzerland)
AC Immune
Research
Dr. Afroz’s research has focused on understanding molecular mechanisms of neurodegeneration and pathways for therapeutic interventions in various CNS indications. At AC Immune, Dr. Afroz serves as Team and project leader for TDP-43 antibody therapeutic program. Prior to joining AC Immune in 2017, Dr. Afroz was a post-doctoral scientist at the University of Zürich where he investigated the pathways that trigger aggregation of ALS/FTD-linked proteins, the mechanisms of neurotoxicity and the molecular basis of disease heterogeneity. Dr. Afroz obtained his master’s degree in Biotechnology at the Indian Institute of Technology in Mumbai. In 2013, he obtained his Ph.D. in Molecular Biology and Biophysics at ETH Zürich where he studied the role of sequence-specific protein-RNA interactions in RNA processing and metabolism.

Presenter of 1 Presentation

 Conference Calendar

TDP-43 IMMUNOTHERAPY DECREASES NEUROPATHOLOGY AND CONFERS NEUROPROTECTION THROUGH MICROGLIAL ENGAGEMENT IN MOUSE MODELS OF ALS/FTD

Session Name
1070 - FTD, ALS; C9ORF72, TDP-43 AND PROGRANULIN (ID 52)
Session Type
SYMPOSIUM
Date
Fri, 18.03.2022
Session Time
09:10 AM - 10:55 AM
Room
ONSITE: 113
Lecture Time
10:10 AM - 10:25 AM
Presenter

Abstract

Aims

Accumulation of pathological transactive response DNA binding protein 43 (TDP-43) into intracellular inclusions underlies frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS) as well as the newly defined limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 inclusions are also present as co-pathology in other neurodegenerative diseases including Alzheimer’s disease. However, no therapeutic interventions targeting TDP-43 pathology are in clinical development. Antibody-mediated clearance of misfolded TDP-43 by microglia and inhibition of cell-to-cell protein spreading represents an attractive strategy for therapeutic intervention.

Methods

Monoclonal antibodies (mAbs) were generated against various regions of TDP-43 using AC Immune’s proprietary SupraAntigenTM platform and selected for evaluation in cell-based and mouse models of TDP-43 proteinopathies.

Results

From a panel of mAbs, ACI-5891 binding to the C-terminal domain of TDP-43 was identified to substantially reduce de novo and templated TDP-43 aggregation induced by FTLD-TDP brain extracts. In rNLS8 transgenic mouse model of ALS and FTLD-TDP, ACI-5891 significantly reduced the levels of phosphorylated TDP-43 (pTDP-43) and insoluble TDP-43 in the brain with a concomitant increase in hypertrophic microglia without induction of inflammation. These outcomes translated into a significant neuroprotective effect in a second mouse model induced by inoculation of FTLD-TDP brain extracts and correlated with significant increase of mAb-mediated TDP-43 aggregate uptake by microglia in vitro.

Conclusions

Our findings demonstrate for the first time that a mAb specific for the C-terminal region of TDP-43 enables clearance of misfolded TDP-43 in vivo through microglia engagement thus limiting pathology progression and conferring neuroprotection. These results support the clinical assessment of TDP-43 immunotherapy.

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