Delivery of therapeutic compounds to the brain and other tissues
The present invention relates to the intrathecal (IT) administration of recombinant enzyme to treat lysosomal storage disorders. In an exemplary embodiment, intrathecal administration of human α-L-iduronidase (rhIDU) injections in MPS I affected animals resulted in significant enzyme uptake, significant rh-iduronidase activity in brain and meninges and a decrease of glycosaminoglycan (GAG) storage in cells of MPS I subjects to that of normal subjects. Intrathecal administration proved more effective than intravenous treatment at alleviating MPS I symptoms, indicating it is a useful method of treating lysosomal storage disorders.
1. A method for treating Sanfilippo syndrome type B (Mucopolysaccharidosis type IIIB or MPS IIIB) comprising the step of administering intrathecally to a human subject in need of treatment a pharmaceutical composition comprising a fusion protein comprising recombinant human α-N-acetylglucosaminidase and a moiety that facilitates high uptake of a lysosomal enzyme, wherein the moiety is an IGF-II polypeptide that allows the lysosomal enzyme to bind to the mannose-6-phosphate receptor, and wherein the fusion protein is administered in an amount effective to ameliorate one or more central nervous system (CNS) symptoms of Sanfilippo syndrome type B.
2. The method of claim 1 , wherein the intrathecal administration results in delivery of the fusion protein to one or more target brain tissues.
3. The method of claim 2 , wherein the fusion protein is delivered to neurons, glial cells, perivascular cells and/or meningeal cells.
4. The method of claim 1 , wherein the intrathecal administration results in reduction of lysosomal storage in brain target tissues.
5. The method of claim 1 , wherein the intrathecal administration results in increased the fusion protein enzymatic activity in brain target tissues.
6. The method of claim 1 , wherein the intrathecal administration results in reduced intensity, severity or frequency, or delayed onset, of at least one symptom or feature of MPS IIIB.
7. The method of claim 6 , wherein the at least one symptom or feature of MPS IIIB is hearing loss, delayed speech development, deficits in motor skills, and/or mental retardation.
8. The method of claim 1 , wherein the intrathecal administration takes place at an interval selected from once every week, once every month, and once every two months.
9. The method of claim 1 , wherein the intrathecal administration is used in conjunction with intravenous administration.
10. The method of claim 1 , wherein the intrathecal administration is not used in conjunction with intravenous administration.
11. The method of claim 1 , wherein the intrathecal administration is used with immunosuppressive therapy.
12. The method of claim 1 , wherein the intrathecal administration is used in absence of concurrent immunosuppressive therapy.