Methods of treating lysosomal storage disorders
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 a lysosomal storage disorder in a patient suffering from a lysosomal storage disorder, comprising administering to the patient ambroxol, ambroxol hydrochloride, or bromhexine, or a pharmaceutically acceptable salt thereof at a dose of 250-500 mg administered once, twice, three or four times a day, wherein said lysosomal storage disorder is characterized by a mutant enzyme having reduced residual catalytic activity in the lysosome due to retention of the mutant enzyme in the endoplasmic reticulum.
2. The method of claim 1 , comprising administering ambroxol or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein said patient is also administered another drug for the treatment of Gaucher's Disease.
4. The method of claim 2 , wherein said patient is also administered another drug for the treatment of Parkinson's Disease.
5. The method of claim 2 , wherein said patient has Gaucher's Disease.
6. The method of claim 5 , wherein said patient also has Parkinson's disease.
7. The method of claim 1 , wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase.
8. The method of claim 1 , wherein the ambroxol derivative is bromhexine or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein said patient is also administered another drug for the treatment of Gaucher's Disease.
10. The method of claim 8 , wherein said patient is also administered another drug for the treatment of Parkinson's Disease.
11. The method of claim 8 , wherein said patient has Gaucher's Disease.
12. The method of claim 11 , wherein said patient also has Parkinson's Disease.
13. The method of claim 8 , wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase.
14. The method of claim 1 , wherein the ambroxol derivative is ambroxol hydrochloride.
15. The method of claim 14 , wherein said patient is also administered another drug for the treatment of Gaucher's Disease.
16. The method of claim 14 , wherein said patient is also administered another drug for the treatment of Parkinson's Disease.
17. The method of claim 14 , wherein said patient has Gaucher's Disease.
18. The method of claim 17 , wherein said patient also has Parkinson's disease.
19. The method of claim 14 , wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase.
20. The method of claim 19 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. 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.
21. The method of claim 20 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S.
22. The method of claim 20 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P.
23. The method of claim 19 , wherein the patient is also administered a recombinant glucocerebrosidase.
24. The method of claim 23 , wherein the recombinant glucocerebrosidase is imiglucerase.
25. The method of claim 1 , wherein patient has a mutation in the gene encoding a beta glucocerebrosidase 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. 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.
26. The method of claim 25 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S.
27. The method of claim 25 , wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P.
28. The method of claim 25 , wherein the patient is also administered a recombinant glucocerebrosidase.
29. The method of claim 28 , wherein the recombinant glucocerebrosidase is imiglucerase.