Compositions useful for treating GM1 gangliosidosis

Abstract

A therapeutic regimen useful for treating GM1 gangliosidosis is provided, which comprises administering a recombinant adeno-associated virus (rAAV) vector having an AAV capsid and a vector genome including a sequence encoding human β-galactosidase. Also provided are compositions containing the rAAV vector and methods for treating GM1 gangliosidosis in patients, which comprise administering the rAAV vector.

Claims

1. A pharmaceutical composition for use in the treatment of GM1 gangliosidosis in human patients, comprising a recombinant adeno-associated virus (rAAV) vector having an AAV capsid and a vector genome containing a sequence encoding human β-galactosidase under the control of a regulatory sequence that directs its expression in target cells, The sequence encoding the human β-galactosidase includes SEQ ID NO: 8 or a sequence that is at least 95% identical thereto, and the expression control sequence includes a ubiquitin C (UbC) promoter, a chimeric intron, and a poly(A) signal. The aforementioned rAAV is (i) When the patient is approximately 1 month to 4 months old, approximately 1.6 × 10 13 ~Approx. 1.6×10 14 GC, (ii) When the patient is at least 4 months old and less than 8 months old, approximately 2.1 × 10 13 ~Approx. 2.1×10 14 GC, (iii) When the patient is at least 8 months old to a maximum of 12 months old, approximately 2.6 × 10 13 ~Approx. 2.6×10 14 GC, or (iv) If the patient is at least 12 months old, approximately 3.2 × 10 13 ~Approx. 3.2×10 14 GC It is administered by a single-dose intracisional cisterna macrocephala (ICM) injection, At least one immunosuppressive combination therapy is administered to the human patient at least one day before or on the day of delivery of the rAAV, and the immunosuppressive combination therapy includes oral prednisolone administered at approximately 1 mg / kg body weight. The aforementioned pharmaceutical composition.

2. (i) The human β-galactosidase coding sequence includes the nucleotide sequence shown in Sequence ID No. 8, (ii) The vector genome further comprises a 5' inverted terminal repeat (ITR) sequence and a 3' ITR sequence, and / or (iii) The pharmaceutical composition for use according to claim 1, wherein the patient is identified as having type 1 (infant) GM1 or type 2a (late infant) GM1.

3. The pharmaceutical composition for use according to claim 1 or claim 2, wherein the administration of the at least one immunosuppressive combination therapy is continued for at least 3 to 4 weeks after the administration of the rAAV.

4. A pharmaceutical composition for use according to any one of claims 1 to 3, wherein the effectiveness of the treatment is evaluated by one or more of the following: delay in the onset of seizures, reduction in the frequency of seizures, β-galactosidase in serum and / or cerebrospinal fluid, and volume changes of brain tissue measured by magnetic resonance imaging (MRI).

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