The invention relates to pharmaceutical compositions, kits, methods, and uses for the treatment of amyotrophic lateral sclerosis. In particular, the invention relates to pharmaceutical compositions, kits, methods, and uses for the treatment of amyotrophic lateral sclerosis by decreasing the expression of a cytoplasmic granule toxin in astrocytes of a patient, or by increasing the expression of MHC class I in motor neurons of the patient.

Compositions and methods are provided for the cell-mediated targeted killing of diseased cells based on the presence of an intracellular antigen, rather than a surface-bound marker. The targeting cells are modified to express a cytotoxic protein that is delivered into a targeted cell, and after delivery is selectively activated by the presence of a cytoplasmic protein of interest. In one embodiment of the invention, the cytotoxic molecule is a Granzyme B (GrB) polypeptide. In the compositions of the invention, GrB is modified to render its cytotoxic enzymatic functions inactive, until the presence of an intracellular antigen unlocks the GrB molecule to enable enzymatic activities.