TREATMENT OF SANFILIPPO SYNDROME TYPE B
Among other things, the present invention provides methods and compositions of treating Sanfilippo syndrome type B (Sanfilippo B) by, e.g., intrathecal (IT) administration of a Naglu protein. A suitable Naglu protein can be a recombinant, gene-activated or natural protein. In some embodiments, a suitable Naglu protein is a recombinant Naglu protein. In some embodiments, a recombinant Naglu protein is a fusion protein containing a Naglu domain and a lysosomal targeting moiety. In some embodiments, the lysosomal targeting domain is an IGF-II moiety.
1 . A method of treating Sanfilippo syndrome type B (San B) disease comprising a step of
administering a pharmaceutical composition to the central nervous system of a subject in need of treatment comprising a recombinant fusion protein comprising alpha-N-acetylglucosaminidase (Naglu) protein, a lysosomal targeting moiety, and a linker between the lysosomal targeting moiety and the Naglu domain.
2 . The method of claim 1 , wherein the administration is intraparenchymal, intracerebral, intraventricular cerebral or intrathecal.
3 - 11 . (canceled)
12 . The method of claim 1 , wherein the linker comprises one or more amino acid sequences of GGGGGAAAAGGGG (SEQ ID NO:4).
13 . (canceled)
14 . The method of claim 1 , wherein the linker further comprises one or more GAP sequences.
15 . The method of claim 1 , wherein the linker comprises amino acid sequence of
(SEQ ID NO: 5)
GAPGGGGGAAAAGGGGGAPGGGGGAAAAGGGGGAPGGGGGAAAAGGGGGA
P.
16 - 19 . (canceled)
20 . The method of claim 1 , wherein the administration results in delivery of the Naglu protein in one or more target brain tissues.
21 . The method of claim 20 , wherein the one or more target brain tissues are selected from the group consisting of tissues from gray matter, white matter, periventricular areas, pia-arachnoid, meninges, neocortex, cerebellum, deep tissues in cerebral cortex, molecular layer, caudate/putamen region, midbrain, deep regions of the pons or medulla, and combinations thereof.
22 . The method of claim 20 , wherein the Naglu protein is delivered to neurons, glial cells, perivascular cells and/or meningeal cells.
23 . The method of claim 20 , wherein the Naglu protein is further delivered to the neurons in the spinal cord.
24 . The method of claim 1 , wherein the administration further results in systemic delivery of the Naglu protein in peripheral target tissues.
25 . The method of claim 24 , wherein the peripheral target tissues are selected from liver, kidney, and/or heart.
26 . The method of claim 1 , wherein the administration results in lysosomal localization in brain target tissues, spinal cord neurons and/or peripheral target tissues.
27 . The method of claim 1 , wherein the administration results in reduction of lysosomal storage in the brain target tissues, spinal cord neurons and/or peripheral target tissues.
28 . The method of claim 27 , wherein the lysosomal storage is determined by LAMP-1 staining.
29 . (canceled)
30 . The method of claim 1 , wherein the administration results in reduced vacuolization in neurons.
31 . (canceled)
32 . The method of claim 1 , wherein the administration results in increased Naglu enzymatic activity in the brain target tissues, spinal cord neurons and/or peripheral target tissues.
33 - 46 . (canceled)
47 . The method of claim 1 , wherein the Naglu fusion protein is administered at a concentration greater than approximately 20 mg/ml.
48 . A therapeutic fusion protein comprising
a Naglu domain;
a lysosomal targeting moiety, and
wherein, once administered, the therapeutic fusion protein is targeted to lysosomes and is therapeutically active in vivo.
49 - 53 . (canceled)
54 . The therapeutic fusion protein of claim 48 , wherein the fusion protein further comprises a linker between the Naglu domain and the lysosomal targeting moiety.
55 . The therapeutic fusion protein of claim 54 , wherein the linker comprises amino acid sequence of
(SEQ ID NO: 4)
GAPGGGGGAAAAGGGGGAPGGGGGAAAAGGGGGAPGGGGGAAAAGGGGGA
P.
56 . (canceled)
57 . A therapeutic fusion protein comprising an amino acid sequence at least 90% identical to SEQ ID NO:5 (the full-length Naglu-IGF-II fusion protein), wherein, once administered, the therapeutic fusion protein is targeted to lysosomes and is therapeutically active in vivo.