Methods and compositions for CNS delivery of arylsulfatase A
Provided are methods of treating metachromatic leukodystrophy comprising administering to a subject in need of treatment a therapeutically effective amount of recombinant arylsulfatase A enzyme.
1. A method of treating metachromatic leukodystrophy (MLD) comprising
determining brain lesion involvement using magnetic resonance imaging (MRI) to obtain an MLD MRI severity score,
administering intrathecally to a subject in need of treatment a recombinant arylsulfatase A (ASA) enzyme at a therapeutically effective dose of greater than 100 mg and an administration interval for a treatment period of at least 6 months sufficient to stabilize or reduce brain lesion involvement relative to baseline; and
assessing brain lesion involvement by the MLD MRI severity score.
2. The method of claim 1 , wherein administering the recombinant ASA enzyme results in stabilization of the MLD MRI severity score in the subject relative to baseline.
3. The method of claim 1 , wherein the subject is human.
4. The method of claim 1 , wherein the treatment interval is at least weekly.
5. The method of claim 1 , wherein the administration interval is every other week.
6. The method of claim 1 , wherein the therapeutically effective dose is less than 200 mg.
7. The method of claim 1 , further comprising determining levels of a biomarker that is decreased in MLD in a brain tissue relative to a baseline level of the biomarker.
8. The method of claim 7 , wherein the biomarker is N-acetylaspartate (NAA).
9. The method of claim 8 , wherein levels of N-acetylaspartate (NAA) are assessed by proton magnetic resonance spectroscopy.
10. The method of claim 9 , further comprising measuring NAA/creatine metabolite ratio.
11. The method of claim 1 , wherein administering the recombinant ASA enzyme results in decreased levels of a biomarker that accumulates in MLD in a bodily fluid selected from the group consisting of cerebrospinal fluid, urine, blood, and blood serum relative to a baseline level of the biomarker.
12. The method of claim 11 , wherein the biomarker is selected from the group consisting of sulfatide, lysosulfatide, and combinations thereof.
13. The method of claim 12 , wherein administering the recombinant ASA enzyme results in a decrease of sulfatide levels in the cerebrospinal fluid (CSF) relative to baseline.
14. The method of claim 1 , wherein administering the recombinant ASA enzyme further results in improvement, stabilization or reduction decline of one or more cognitive, adaptive, and/or executive functions.
15. The method of claim 1 , wherein the subject is 16 years old or younger.
16. The method of claim 1 , wherein the subject is three years old or younger.