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 of reducing the symptoms of Gaucher's Disease in an individual suffering from Gaucher's Disease comprising administering to said individual (i) ambroxol, bromhexine, or a pharmaceutically acceptable salt thereof, and (ii) another drug for the treatment of Gaucher's Disease.
2. The method according to claim 1 comprising administering bromhexine, or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 comprising administering ambroxol or a pharmaceutically acceptable salt thereof.
4. The method according to claim 3 comprising administering ambroxol hydrochloride.
5. The method according to claim 1 wherein said (i) ambroxol, bromhexine, or pharmaceutically acceptable salt thereof and (ii) said other drug are administered simultaneously.
6. The method according to claim 1 wherein said (i) ambroxol, bromhexine, or pharmaceutically acceptable salt thereof and (ii) said other drug are administered at different times.
7. The method according to claim 1 wherein said (i) ambroxol, bromhexine, or pharmaceutically acceptable salt thereof and (ii) said other drug are administered by the same route.
8. The method according to claim 1 wherein said (i) ambroxol, bromhexine, or pharmaceutically acceptable salt thereof and (ii) said other drug are administered by different routes.
9. The method of claim 1 , wherein the Gaucher's Disease is characterized by a mutation in the gene encoding a beta-glucocerebrosidase.
10. The method of claim 9 , wherein the mutation in the gene encoding a beta-glucocerebrosidase is selected from:
a. A point mutation comprising V15L, G46E, K79N, R119Q, P122S, R131L, K157Q, N188S, Y212H, F213I, F216V, F216Y, F251L, R257E, P289L, A309V, H311R, W312C, Y323I, 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. QA 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.
11. The method of claim 10 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S.
12. The method of claim 10 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P.
13. The method of claim 1 , wherein the another drug for the treatment of Gaucher's Disease is recombinant glucocerebrosidase.
14. The method of claim 13 , wherein the recombinant glucocerebrosidase is imiglucerase.