RNA interference for the treatment of gain-of-function disorders
The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.
1. A method of treating or managing Huntington's disease, comprising administering to the patient in need of such treatment or management a therapeutically effective amount of a vector that expresses an effective amount of an engineered RNA precursor targeting UAAGAGAUGGGGACAGUACUUCAACGCUAGAAGAACA (SEQ ID NO: 43) of the Htt mRNA, such that RNA silencing of said mRNA occurs, wherein the engineered RNA precursor comprises (i) an antisense strand or a variant thereof having sufficient complementarity to SEQ ID NO: 43 to direct target-specific cleavage or translational repression of the Htt mRNA; and (ii) a sense strand or a variant thereof that is substantially complementary to the antisense strand, such that the sense and antisense strands are capable of annealing together.
2. The method of claim 1 , wherein the vector is a viral vector, retroviral vector, expression cassette, or plasmid.
3. The method of claim 1 , wherein the vector further comprises an RNA Polymerase III or RNA Polymerase II promoter.
4. The method of claim 3 , wherein the RNA Polymerase III promoter is the U6 or H1 promoter.
5. The method of claim 1 , wherein the engineered RNA precursor contains at least one internal bulge.
6. The method of claim 1 , wherein each strand of the engineered RNA precursor is between 15 and 50 base pairs in length.