Targeting The Root Cause of ALS, Pathogenic TDP-43

The formation of misfolded TAR DNA binding protein 43 (TDP-43) inside neurons is often associated with the development of amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE).

About TDP-43

TDP-43 is normally present in the nucleus of all cells and performs an essential role in neuronal cell survival. Therefore, the targeting of pathogenic TDP-43 requires strict selectivity for the misfolded form of the protein to potentially avoid safety concerns. Currently, we have several lead program candidates that have shown the desired selectivity for misfolded TDP-43 as well as an initial functional benefit in blocking prion-like propagation and/or clearing aggregated TDP-43 from cells.

Misfolded Protein Targets for ALS

Misfolded Protein Target Lead Indication Other Indications Status
TDP-43 ALS FTD, LATE Lead Antibodies
SOD1 ALS Lead Antibodies
RACK1 ALS HD, Cancers Antibody Screening
Ataxin2 ALS Immunizations
Disc1 Schizophrenia Computational Modeling

PMN267: TDP-43 Program Key Features

Our TDP-43 program for ALS features potential advantages, including:

  • Multiple antibodies with target selectivity
    • Binds to toxic misfolded TDP-43, not normal physiologic TDP-43
  • Potential functional benefit both as extracellular antibody and intracellular intrabody
    • Extracellular antibody candidate shows functional benefit in blocking prion-like propagation in vitro.
    • Intrabody candidates targeting intracellular misfolded TDP-43 feature:
      • High-affinity binding
      • Selectivity for toxic TDP-43
      • No apparent detrimental impact on cell viability
      • Clearance of pathogenic aggregates from inside cells
  • Potential synergistic portfolio for ALS disease-modifying treatment with other ProMIS targets: a-synuclein, RACK1, and SOD1.

Screening and Validation for ALS Candidates

Experimentally, misfolded aggregates of TDP-43 are toxic to neural cells. Identification of epitopes present on misfolded TDP-43 through the ProMIS discovery platform allowed for the generation of high affinity antibodies showing selective recognition of misfolded cytoplasmic aggregates of TDP-43 with no detectable interaction with normal TDP-43 which is located in the nucleus and is important for normal cell function. The antibodies also recognized and stained pathogenic TDP-43 aggregates in spinal cord sections from ALS patients and brain sections from FTLD patients indicating that they have the potential to target disease-causing TDP-43 in these patients. In vitro data showed that such antibodies can inhibit the cell to cell transmission of misfolded TDP-43 in the extracellular space thereby offering the potential to inhibit spreading of pathology.

Harnessing the Molecular Species Selectivity of Antibodies

There are two basic approaches to antibody-based targeting of pathogenic TDP-43:

  • Extracellular antibody
    • Antibodies delivered outside the cell inhibit cell-to-cell transmission of misfolding TDP-43 aggregates.
  • Vectorized intrabody delivered inside the cell with a gene therapy vector
    • ProMIS intrabodies are highly selective, interacting only with cytoplasmic TDP-43 aggregates and not normal nuclear TDP-43
      • Expression of TDP-43 intrabody is not toxic to cells.
      • Intrabody co-localizes with mislocalized, aggregated cytoplasmic TDP-43 and promotes their clearance.
      • Intrabody does not interact with endogenous normal TDP-43 in the nucleus.

Development Status

The next step is selection of lead antibody and intrabody candidates for producer cell line and vector development.

Our Lead Program: PMN310 for Alzheimer’s

PMN310 selectively binds to the toxic misfolded forms of amyloid-beta, a protein commonly associated with the development of Alzheimer’s disease. Preclinical studies of PMN310 have shown greater selectivity in binding to the toxic misfolded oligomers of Aβ protein than has been shown with other amyloid-focused antibody therapies currently in clinical development.

Alpha-synuclein Programs for Parkinson’s

Studies indicate that alpha-synuclein (α-Syn) plays a key role in the development of Parkinson’s disease (PD) and other neurodegenerative disorders. We are working to identify product candidates that show high selectivity for misfolded α-Syn and potential benefits in reducing the neurotoxicity and propagation of misfolded α-Syn

Scientific Posters & Publications

Our scientific expertise is backed by decades of research on protein misfolding diseases such as AD, MSA, ALS, and PD. We encourage you to visit our scientific library to learn more about our programs.

View Posters & Publications