Methods and compositions for CNS delivery of iduronate-2-sulfatase
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 iduronate-2-sulfatase (I2S) protein, salt, and a polysorbate surfactant for the treatment of Hunters Syndrome.
1. A method of treating Hunter Syndrome comprising a step of
administering intrathecally to a human subject in need of treatment a formulation comprising iduronate-2-sulfatase (I2S) at a concentration of at least 10 mg/ml and no greater than 5 mM phosphate, and wherein the I2S is administered at a dose amount of at least 10 mg.
2. 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.
3. The method of claim 1 , wherein the step of administering intrathecally results in no substantial adverse effects in the subject.
4. The method of claim 1 , wherein the intrathecal administration of the formulation results in delivery of the I2S protein to target brain tissues.
5. The method of claim 4 , wherein the target brain tissues comprise white matter and/or gray matter.
6. The method of claim 4 , wherein the I2S protein is delivered to neurons, glial cells, perivascular cells and/or meningeal cells.
7. The method of claim 4 , wherein the I2S protein is further delivered to the neurons in the spinal cord.
8. 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.
9. The method of claim 8 , wherein the peripheral target tissues are selected from liver, kidney, and/or heart.
10. The method of claim 1 , wherein the intrathecal administration of the formulation results in reduction of GAG 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 vacuolization in neurons.
12. The method of claim 1 , wherein the intrathecal administration of the formulation results in increased I2S enzymatic activity in the 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 Hunter Syndrome.
14. The method of claim 13 , wherein the at least one symptom or feature of the Hunter Syndrome is cognitive impairment; white matter lesions; dilated perivascular spaces in the brain parenchyma, ganglia, corpus callosum, and/or brainstem; atrophy; and/or ventriculomegaly.
15. The method of claim 1 , wherein the intrathecal administration takes place at an interval selected from once every two weeks, once every month, and once every two months.
16. The method of claim 1 , wherein the intrathecal administration is used in conjunction with 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 I2S protein is a synthetic, recombinant, gene-activated or natural enzyme.
19. The method of claim 1 , wherein the I2S protein is present at a concentration of approximately 25 mg/ml.
20. The method of claim 10 , wherein the GAG storage is reduced by at least 20% as compared to an untreated control.
21. The method of claim 12 , wherein the I2S enzymatic activity is increased by at least 1-fold as compared to an untreated control.
22. The method of claim 12 , wherein the increased I2S enzymatic activity is at least approximately 10 nmol/hr/mg.
23. The method of claim 12 , wherein the I2S enzymatic activity is increased in the lumbar region.
24. The method of claim 4 , wherein the target brain tissue is a deep brain tissue at least 4 mm below the surface of the cerebrum.
25. The method of claim 11 , wherein the neurons comprise Purkinje cells.
26. The method of claim 1 , wherein the formulation is administered in a volume of about 1-5 ml.
27. The method of claim 1 , wherein the intrathecal administration is sustained release.