Gene therapy for neurodegenerative disorders
AssigneeGenzyme Corporation
InventorsMarco A. Passini, Lamya Shihabuddin, Seng H. Cheng
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Abstract
Compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and/or spinal cord, are disclosed.
Claims21
A method of modulating motor function in a subject with spinal muscular atrophy (SMA) comprising administering to a subject in need thereof a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) virion comprising a self-complementary adeno-associated virus (scAAV) vector comprising a heterologous nucleic acid construct, wherein the heterologous nucleic acid construct comprises:
- a. a first AAV2 inverted terminal repeat (ITR);
- b. a cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- c. a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- and
- d. a second AAV2 ITR,
- wherein the rAAV virion comprises an AAV8 or AAV9 capsid, and wherein the rAAV virion is administered (i) via direct spinal cord injection, and/or (ii) via intrathecal injection.
A method of treating spinal muscular atrophy (SMA) comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR;
- a cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- a second AAV2 ITR;
- an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
A method of increasing survival of a subject, comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the subject has spinal muscular atrophy (SMA), wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR;
- a cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- a second AAV2 ITR;
- an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
A method of expressing a survival motor neuron (SMN) protein in motor neurons of the spinal cord, comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the subject has spinal muscular atrophy (SMA), wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR;
- a cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- a second AAV2 ITR;
- an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:
- 2;
- an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
- and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
Dependencies are inferred from the claim text.