Claims for Patent: 10,028,922

Summary for Patent: 10,028,922

Title:	Method for enhancing folding and transport of misfolded glucocerebrosidase
Abstract:	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.
Inventor(s):	Mahuran; Don J. (Toronto, CA), Tropak; Michael B. (Toronto, CA), Buttner; Justin D. (Rosehill, AU), Blanchard; Jan E. (St. Catherines, CA), Brown; Eric D. (Oakville, CA)
Assignee:	The Hospital for Sick Children (Ontario, CA) McMaster University (Ontario, CA)
Application Number:	15/223,312
Patent Claims:	1. A method of enhancing transport of misfolded GCase to a lysosome in a patient suffering from Gaucher's Disease, comprising administering to said patient ambroxol 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 ambroxol or bromhexine or a pharmaceutically acceptable salt thereof enhances transport of the misfolded GCase to the lysosome. 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 has Gaucher's Disease. 5. The method of claim 2, wherein the patient is also administered a recombinant glucocerebrosidase. 6. The method of claim 5, wherein the recombinant glucocerebrosidase is imiglucerase. 7. The method of claim 2, wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase. 8. The method of claim 7, 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+IG-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 IVSI 0 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. 11. The method of claim 8, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises E326K. 12. The method of claim 1, comprising administering ambroxol hydrochloride. 13. The method of claim 12, wherein said patient is also administered another drug for the treatment of Gaucher's Disease. 14. The method of claim 12, wherein the patient is also administered a recombinant glucocerebrosidase. 15. The method of claim 14, wherein the recombinant glucocerebrosidase is imiglucerase. 16. The method of claim 12, wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase. 17. The method of claim 16, 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+IG-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 IVSI 0 and deletion of the first 11 base pairs of exon 11. 18. The method of claim 17, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S. 19. The method of claim 17, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P. 20. The method of claim 17, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises E326K. 21. The method of claim 1, comprising administering bromhexine or a pharmaceutically acceptable salt thereof. 22. The method of claim 21, wherein said patient is also administered another drug for the treatment of Gaucher's Disease. 23. The method of claim 21, 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 21, wherein said patient has a mutation in the gene encoding a beta glucocerebrosidase. 26. The method of claim 25, 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+IG-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 IVSI 0 and deletion of the first 11 base pairs of exon 11. 27. The method of claim 26, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises N370S. 28. The method of claim 26, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises L444P. 29. The method of claim 26, wherein the mutation in the gene encoding a beta-glucocerebrosidase comprises E326K.

Details for Patent 10,028,922

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CEREZYME	imiglucerase	For Injection	020367	May 23, 1994		2027-09-17
Genzyme Corporation	CEREZYME	imiglucerase	For Injection	020367	September 22, 1999		2027-09-17