The United States of America, As Represented by the Secretary, Department of Health and Human Services

Randy J Chandler

Charles P Venditti

William J Pavan

John A Chiorini

Giovanni Di Pasquale

Provided herein are compositions and methods for the viral gene therapy (e.g., AAV-directed gene therapy) of cholesterol storage diseases or disorders, such as Niemann-Pick disease, Type C.

Viral gene therapy as treatment for cholesterol storage disease or disorder

The present disclosure provides compositions for viral gene therapy, e.g. Adeno-Associated virus-directed gene therapy, and methods of using the same for the treatment and/or prevention of cholesterol storage diseases or disorders, such as Niemann-Pick disease, Type C.

Codon-optimized human NPC1 genes for the treatment of Niemann-Pick type C1 deficiency and related conditions

The invention provides an adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence, and wherein the heterologous nucleic acid sequence can encode the NGF-PTH fusion polypeptide or methylmalonyl CoA mutase enzyme. The invention also provides a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH), wherein the polypeptide can comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. The invention provides a nucleic acid encoding the polypeptide, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid, or vector, as well as treatment methods comprising the polypeptide, nucleic acid, vector, or composition. The invention further provides a method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering an AAV vector comprising a heterologous nucleic acid sequence encoding methylmalonyl CoA mutase enzyme to the mammal.

AAV with unique capsid protein VP1 and methods of using for treatment

Synthetic polynucleotides encoding human methylmalonyl-CoA mutase (synMUT) and exhibiting augmented expression in cell culture and/or in a subject are described herein. An adeno-associated viral (AAV) gene therapy vector encoding synMUT under the control of a liver-specific promoter (AAV2/8-HCR-hAAT-synMUT-RBG) successfully rescued the neonatal lethal phenotype displayed by methylmalonyl-CoA mutase-deficient mice, lowered circulating methylmalonic acid levels in the treated animals, and resulted in prolonged hepatic expression of the product of synMUT transgene in vivo, human methylmalonyl-CoA mutase (MUT).

Synthetic methylmalonyl-CoA mutase transgene for the treatment of MUT class methylmalonic acidemia (MMA)

The invention provides a device including a chamber wherein the chamber including a rigid enclosure; a rigid lid for the enclosure; a gasket between the lid and the enclosure to allow for an airtight seal between the enclosure and the gasket upon closure of a latch connecting the enclosure and the lid; a port for airtight attachment of a syringe, and a port for airtight insertion of a gas sensor. The device can further include a gas sensor and one or more syringes for attachment to the device by a three-way stopcocks. The device is appropriately sized for use with the subject of interest. The invention also provides methods for use of the device.

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Washington, DC, United States of America

Randy J Chandler