The J. David Gladstone Institutes

Erik Roberson

Lennart Mucke

Li Gan

Sarah Mueller-Steiner

The present invention provides methods of identifying candidate agents for treating excitotoxicity-related disorders. The present invention further provides methods for treating excitotoxicity-related disorders.

Agents that reduce neuronal overexcitation

Agents that reduce the level of a tau gene product in a cell, e.g., in a neuron, include antisense nucleic acids. For example, antisense nucleic acids can be used to down-regulate expression of a tau gene in a cell (e.g., in a neuron). The antisense sequence is complementary to the mRNA of the targeted gene (e.g., tau), and inhibits expression of the targeted gene products. Suitable oligonucleotides can be chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. A number of such modifications have been described in the literature, which modifications alter the chemistry of the backbone, sugars, or heterocyclic bases.

The present invention provides a method of increasing cathepsin B-induced cleavage of amyloid-&#x3b2; (A&#x3b2;) peptide in a cell or tissue, the method generally involving contacting the cell or tissue with an agent that increases the level of cathepsin B in the cell or tissue. The present invention further provides variant cathepsin B polypeptides that are resistant to inhibition by a cysteine protease inhibitor; as well as nucleic acids encoding the variants, and host cells comprising the nucleic acids.

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Vestavia Hills, AL, United States of America

Erik Roberson