How does TDP-43 bog up the brains of ALS, FTLD patients? AC Immune enlists Penn scientists to find out
AC Immune, the Swiss biotech known for its tau approach to Alzheimer’s, is shining light on another misfolding protein believed to be responsible for other neurodegenerative diseases in a new research pact with the University of Pennsylvania.
The transactive response (TAR) DNA binding protein, or TDP-43 in short, is found in most human tissues but its misfolded form was identified in 2006 as a common pathologic substance linking frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Researchers have since suggested that when in the wrong shape, the protein activates the “cell autophagy gene” ATG7, which prompts neurons to decompose.
Offering a grant to John Trojanowski and Virginia Lee — co-directors of Penn’s Center for Neurodegenerative Disease Research and a married couple — AC Immune now wants to decipher “the governing principles of how pathological forms of TDP-43 spread from neuron to neuron.” The ultimate goal is to support development of both therapeutic and diagnostic approaches in FTLP and other ailments.
Both renowned in the field of neurodegeneration, Trojanowski and Lee are credited for elucidating the role of protein culprits such as tau, alpha-synuclein, the Abeta precursor protein, and TDP-43 in neurodegenerative diseases.
AC Immune has several antibodies in its arsenal designed to bind to TDP-43 and lined up preclinical proof-of-concept studies set to announce results later this quarter. It’s hinting that TDP-43 might even be a target for Alzheimer’s — an important new avenue to investigate at a time the dominant amyloid beta hypothesis has all but crumbled.
Scientists from the Université Laval in France have generated an antibody candidate. When injected to mice engineered to exhibit symptoms of ALS, the drug appeared to reduce the number of TDP-43 aggregates and decrease inflammation in the brain, while improving the mice’s cognitive and motor performance.
AC Immune also finds at least one other specialist player in the TDP-43 arena. Aquinnah, a biotech based out of Cambridge, MA, has received small but notable investments from Pfizer, AbbVie and Takeda to work on breaking down the protein buildups. It’s also interested in applying these small molecule drugs to tau for Alzheimer’s.
“The field is still investigating the precise causes of neurodegenerative diseases and how to prevent, treat and even cure them, including neuro-orphan indications such as FTLD,” AC Immune CEO Andrea Pfeifer said in a statement. “Increasing our knowledge of the role of TDP-43 in disease pathology will mark valuable progress in this effort.”