Viral vectors for treating neurogenic detrusor overactivity
The present invention provides a method and a pharmaceutical composition for the treatment of the NDO comprising the viral expression vector carrying a transcription cassette that harbors transgene(s) inhibiting/silencing neurotransmission or synaptic transmission of afferent neurons.
1. A herpes simplex virus (HSV) viral expression vector comprising at least:
a) one promoter active selectively in afferent neurons of the bladder, wherein the promoter is a promoter of Calcitonin Gene Related Peptide (CGRP),
b) at least one transcription cassette comprising a nucleotide sequence operably linked to said promoter, wherein said nucleotide sequence codes for a fusion protein comprising a modified bacterial neurotoxin and a signal peptide domain, wherein the fusion protein is chosen from the group consisting of SEQ ID NO: 28, SEQ ID NO: 30, and SEQ ID NO: 32, wherein said nucleotide sequence inhibits the transduction of the neurotransmitter signal in a postsynaptic cell when transcribed, and
c) a long-term expression (LTE) sequence and a DNA insulator from the HSV-1 genome, wherein said transcription cassette is placed between the LTE sequence and the DNA insulator.
2. The viral expression vector according to claim 1 , wherein said nucleotide sequence inhibits neurotransmission or synaptic transmission of afferent neurons when transcribed by disrupting at least the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex.
3. The viral expression vector according to claim 1 , wherein said viral expression vector codes for a fusion protein comprising a modified bacterial neurotoxin and a signal peptide domain, wherein the fusion protein is chosen from the group consisting of SEQ ID NO: 30 and SEQ ID NO: 32.
4. A pharmaceutical composition comprising at least one viral expression vector according to claim 1 .
5. A Kit comprising at least one viral expression vector according to claim 1 , and an electrical stimulation system comprising electrodes to be implanted on the sacral anterior roots, to apply intermittent stimulation pulse trains in order to achieve a sustained detrusor muscle contraction with intervals of urethral sphincter relaxation allowing urine to flow.
6. The viral expression vector according to claim 1 , wherein said promoter is a promoter of CGRP of SEQ ID NO: 3 or SEQ ID NO: 4.
7. The viral expression vector according to claim 1 , wherein said HSV vector is a HSV-1 vector.
8. A method for the treatment of neurogenic detrusor overactivity comprising administering the pharmaceutical composition of claim 4 to a patient in need thereof.
9. The viral expression vector according to claim 1 , wherein the HSV vector is a defective viral vector derived from HSV.