Antigen-specific immunotherapy with engineered cytotoxic T cells targeting misformed proteins to treat neurodegenerative and muscular diseases.

Neurodegenerative and muscular diseases, such as amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), and Alzheimer’s disease (AD), collectively affect over 5 million adults in the United States. Patients with these diseases suffer from progressive muscle weakening and/or neuron degeneration, which often leads to death; despite extensive research, no effective treatments currently exist. Scientific evidence suggests that antigen-specific T cells may play a role in these diseases, but the development of antigen-specific therapies have been limited by the lack of understanding in the antigen and T cell receptor (TCR) pairs that drive these diseases and difficulties in identifying antigen targets.

In many ALS, IBM, and AD patients, abnormal buildup and dysfunction of a DNA-binding protein causes misformed short proteins called cryptic peptides. These peptides are promising candidates for antigen-specific immunotherapy: antigen-specific TCRs and engineered cytotoxic T cells expressing these TCRs could be used for early detection and/or treatment of neurodegenerative and muscular disorders.

 The inventors identified critical TCR sequences and cryptic peptide antigens, which were then used to engineer cytotoxic T cells to treat various neurodegenerative and muscular diseases. Single cell sequencing was performed to profile TCRs present in donors with ALS and IBM, resulting in identification of antigen-specific TCRs capable of recognizing cryptic peptides. Cytotoxic T cells expressing these TCRs successfully killed abnormal neurons, showing the potential for using these TCRs in T cell-based immunotherapies for neurodegenerative and muscular diseases. These TCRs can be used to generate humanized mouse models to understand disease mechanisms and advance therapies.

Engineered cytotoxic T cells expressing a TCR against a cryptic peptide killed more abnormal neurons compared to a control.
Cryptic peptides are strong candidates for T cells responses as they are not present during T cell selection.
Antigen-specific T cell therapies are an improvement over allogenic T cell therapies.