Method of treating Gaucher disease
Therapeutic compositions and methods for treatment of late-onset Gaucher disease are described herein. The compositions comprise compounds having activity as pharmacological chaperones for mutant forms of the beta-glucocerebrosidase. Methods of treatment involve providing therapeutically effective amounts of such compositions to subjects in need thereof.
1. A method for inducing a stable conformation of a misfolded glucocerebrosidase in a patient with Parkinson's Disease, consisting of administering to the patient a pharmaceutically acceptable amount of ambroxol, ambroxol hydrochloride, or bromhexine or a pharmaceutically acceptable salt thereof, wherein said ambroxol, ambroxol hydrochloride, or bromhexine or a pharmaceutically acceptable salt thereof induces a stable conformation of a misfolded glucocerebrosidase.
2. The method according to claim 1 , wherein the compound is bromhexine, or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 , wherein the compound is ambroxol, or a pharmaceutically acceptable salt thereof.
4. The method according to claim 3 , wherein the compound is ambroxol hydrochloride.
5. The method according to claim 3 , wherein the misfolded glucocerebrosidase is a misfolded beta-glucocerebrosidase.
6. The method according to claim 5 , wherein the misfolded beta-glucocerebrosidase is a wild type glucocerebrosidase.
7. The method according to claim 5 , wherein the misfolded beta-glucocerebrosidase is a mutant glucocerebrosidase.
8. The method of claim 7 wherein the mutant glucocerebrosidase has a mutation selected from:
a. A point mutation comprising V15L, G46E, K79N, R119Q, P122S, R131L, K157Q, N188S, Y212H, F2131, F216V, F216Y, F251L, R257E, P289L, A309V, H311R, W312C, Y3231, G325R, C342G, R353G, R359X (termination), S364T, N370S, L371V, G377S, V394L, V398F, P401L, D409H, D409V, P415R, L444P, R463C, G478S, or R496H;
b. Point mutations at L444P, A456P, and V460V;
c. Point mutations at D140H and E326K;
d. Point mutations at H255Q and D409H;
e. Guanine insertion at 84GG;
f. Splice site mutation in intron 2 (IVS2DS+1G-A), resulting in the skipping of exon 2;
g. A 1-bp deletion (1023delC in the genomic sequence) in the GCase gene, h. A 55-bp deletion (nucleotides 5879-5933 in genomic DNA) in the GCase gene;
i. A homozygous 259C-T transition (1763 in the genomic DNA) j. A homozygous 1-bp deletion in the GCase gene, resulting in a frameshift and premature truncation of the protein in exon 6; and
k. A G-to-A substitution at the first position in the splice site of intron 10 of the GCase gene, resulting in the insertion of the first 11 base pairs of IVS10 and deletion of the first 11 base pairs of exon 11.
9. The method of claim 8 wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S.
10. The method of claim 8 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P.