Methods and compositions for CNS delivery of arylsulfatase A
The present invention provides, among other things, compositions and methods for CNS delivery of lysosomal enzymes for effective treatment of lysosomal storage diseases. In some embodiments, the present invention includes a stable formulation for direct CNS intrathecal administration comprising an arylsulfatase A (ASA) protein, salt, and a polysorbate surfactant for the treatment of Metachromatic Leukodystrophy Disease.
1. A method of treating metachromatic leukodystrophy (MLD) disease comprising a step of
administering intrathecally to a human subject in need of treatment a formulation comprising an arylsulfatase A (ASA) protein at a concentration at or greater than 5 mg/mL and at a dose amount of at least 70 mg/kg brain weight, wherein the formulation comprises no greater than 50 mM of phosphate.
2. The method of claim 1 , wherein the intrathecal administration of the formulation results in no substantial adverse effects in the subject.
3. The method of claim 2 , wherein the intrathecal administration of the formulation results in no substantial adaptive T cell-mediated immune response in the subject.
4. The method of claim 1 , wherein the intrathecal administration of the formulation results in delivery of the ASA protein to oligodendrocytes of deep white brain matter.
5. The method of claim 1 , wherein the ASA protein is delivered to neurons, glial cells, perivascular cells and/or meningeal cells.
6. The method of claim 1 , wherein the ASA protein is further delivered to the neurons in the spinal cord.
7. The method of claim 1 , wherein the intrathecal administration of the formulation further results in systemic delivery of the ASA protein in peripheral target tissues.
8. The method of claim 7 , wherein the peripheral target tissues are selected from liver, kidney, and/or heart.
9. The method of claim 1 , wherein the intrathecal administration of the formulation results in lysosomal localization in target brain tissues, spinal cord neurons and/or peripheral target tissues.
10. The method of claim 1 , wherein the intrathecal administration of the formulation results in reduction of sulfatide storage in target brain tissues, spinal cord neurons and/or peripheral target tissues.
11. The method of claim 1 , wherein the intrathecal administration of the formulation results in reduced progressive demyelination and axonal loss within the CNS and PNS.
12. The method of claim 1 , wherein the intrathecal administration of the formulation results in increased ASA enzymatic activity in target brain tissues, spinal cord neurons and/or peripheral target tissues.
13. The method of claim 1 , wherein the intrathecal administration of the formulation results in reduced intensity, severity, or frequency, or delayed onset of at least one symptom or feature of the MLD disease.
14. The method of claim 13 , wherein at least one symptom or feature of the MLD disease is increased intracranial pressure, hydrocephalus ex vacuo, accumulated sulfated glycolipids in the myelin sheaths in the central and peripheral nervous system and in visceral organs, progressive demyelination and axonal loss within the CNS and PNS, and/or motor and cognitive dysfunction.
15. The method of claim 1 , wherein the intrathecal administration takes place at an interval selected from once every two weeks, once every month, once every two months.
16. The method of claim 1 , wherein the intrathecal administration is used in absence of intravenous administration.
17. The method of claim 1 , wherein the intrathecal administration is used in absence of concurrent immunosuppressive therapy.
18. The method of claim 1 , wherein the formulation comprises NaCl at a concentration of approximately 154 mM, polysorbate 20 at a concentration of approximately 0.005%, and a pH of approximately 6.
19. The method of claim 1 , wherein the ASA protein is a synthetic, recombinant, gene-activated or natural enzyme.
20. The method of claim 1 , wherein the ASA protein is present at a concentration of at least about 10 mg/mL.
21. The method of claim 1 , wherein the ASA protein is present at a concentration of at least about 50 mg/mL.
22. The method of claim 10 , wherein the sulfatide storage is reduced by at least 20% as compared to an untreated control.
23. The method of claim 12 , wherein the increased ASA enzymatic activity is at least 1-fold as compared to untreated control.
24. The method of claim 12 , wherein the increased ASA enzymatic activity is at least 10 nmol/hr/mg.
25. The method of claim 12 , wherein the ASA enzymatic activity is increased in the lumbar region.
26. The method of claim 9 , wherein the target brain tissue is deep brain tissue at least 4 mm below the surface of the cerebrum.
27. The method of claim 9 , wherein the neurons comprise Purkinje cells.
28. The method of claim 1 , wherein the formulation is administered in a volume of less than 3 mL.
29. The method of claim 1 , wherein the dose amount is of at least 80 mg/kg brain weight.
30. The method of claim 1 , wherein the dose amount is of at least 90 mg/kg brain weight.
31. The method of claim 1 , wherein the dose amount is of at least 100 mg/kg brain weight.
32. The method of claim 1 , wherein the arylsulfatase A (ASA) protein is administered intrathecally at a total amount of 100 mg per injection.