Treatment of cognitive impairment of mucopolysaccharidosis type IIIA by intrathecal delivery of heparan N-sulfatase
The present invention provides, among other things, effective treatment for Sanfilippo Syndrome Type A (MPS IIIA) based on intrathecal delivery of recombinant heparan N-sulfatase (HNS) enzyme. The present invention also includes methods of treating Sanfilippo Syndrome Type A (MPS IIIA) Syndrome by intrathecal administration of a recombinant HNS enzyme at a therapeutically effective dose and an administration interval for a period sufficient to decrease glycosaminoglycan (GAG) heparan sulfate level in the cerebrospinal fluid (CSF) relative to baseline (e.g., prior to treatment) as well as to improve, stabilize, or reduce decline of cognitive function, disability, behavior, quality of life and/or auditory brainstem response relative to baseline (e.g., prior to treatment).
1. A method of treating Sanfilippo Syndrome Type A (MPS IIIA) comprising a step of administering intrathecally to a subject in need of treatment a recombinant heparan N-sulfatase (HNS) enzyme at a therapeutically effective dose and an administration interval for a period sufficient to stabilize or reduce decline of cognitive function relative to baseline,
wherein the administration interval is at least once every month;
wherein the therapeutically effective dose is or is greater than 45 mg per dose;
and wherein the period is at least 54 months.
2. The method of claim 1 wherein the administration is through intermittent or continuous access to an implanted intrathecal drug delivery device (IDDD).
3. The method of claim 1 , wherein the cognitive function is assessed by the Bayley Scales of Infant Development (Third Edition) (BSID-III) instrument.
4. The method of claim 3 , wherein the intrathecal administration of the recombinant HNS enzyme results in stabilization of a BSID-III development quotient relative to baseline.
5. The method of claim 1 , wherein the cognitive function is assessed by the Kaufman Assessment Battery for Children (Second Edition) (KABC-II) instrument.
6. The method of claim 5 , wherein the intrathecal administration of the recombinant HNS enzyme results in stabilization of a KABC-II development quotient relative to baseline.
7. The method of claim 1 , wherein the cognitive function is assessed by the Vineland Adaptive Behavior Scales Second Edition (VABS-II) test.
8. The method of claim 7 , wherein the intrathecal administration of the recombinant HNS enzyme results in stabilization of a VABS-II development quotient relative to baseline.
9. The method of claim 1 , wherein the subject in need of treatment is at least 3 years old, at least 12 years old, or at least 18 years old.
10. The method of claim 1 , wherein the method further comprises a step of adjusting the dose and/or administration interval for intrathecal administration based on improvement, stabilization or reduction in decline of cognitive function, relative to baseline.
11. The method of claim 10 , wherein the step of adjusting comprises increasing the therapeutic effective dose for intrathecal administration if the improvement, stabilization or reduction in decline of cognitive function is unaltered or decreased relative to baseline after 4 doses.
12. The method of claim 1 , wherein the intrathecal administration does not require an immunosuppressant.
13. The method of claim 1 , wherein the intrathecal administration is performed in conjunction with intravenous administration of the recombinant HNS enzyme.
14. The method of claim 1 , wherein the subject has cognitive impairment.