Viral gene therapy as treatment for cholesterol storage disease or disorder
Inventors
Venditti, Charles P. • Chandler, Randy • Pavan, William J.
Assignees
US Department of Health and Human Services
Publication Number
US-12201658-B2
Publication Date
2025-01-21
Expiration Date
2036-04-07
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Abstract
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.
Core Innovation
The invention provides compositions and methods for viral gene therapy, specifically using adeno-associated virus (AAV) vectors, to treat cholesterol storage diseases or disorders such as Niemann-Pick disease, type C (NPC). The gene therapy constructs comprise therapeutic human nucleic acid molecules encoding NPC1 or NPC2 genes, operably linked to tissue-specific or constitutive promoters capable of expression in the central nervous system (CNS). Promoters exemplified include neuronal-specific calmodulin-dependent protein kinase II (CaMKII) and elongation factor 1 alpha (EF1α) or variants thereof. The vectors, particularly those based on AAV serotype 9, are designed to cross the blood-brain barrier and deliver NPC1 or NPC2 genes effectively to CNS tissues to restore function lost due to mutations.
Niemann-Pick disease, type C is a fatal autosomal recessive neurodegenerative disorder characterized by mutations primarily in the NPC1 gene, leading to intracellular accumulation of unesterified cholesterol and glycosphingolipids in neuronal tissue, causing hepatosplenomegaly and neurological decline. There is no current curative therapy, and the disease typically presents with progressive ataxia, dementia, seizures, and death usually by the late second or third decade. The background highlights an urgent need for effective treatments that can restore NPC1 function and alleviate pathological cholesterol accumulation in the CNS.
The invention addresses this need by providing gene therapy vectors that deliver functional NPC1 or NPC2 sequences under promoters that allow targeted or broad expression in neuronal and other CNS cell types. The described vectors have been tested in murine models of NPC disease, specifically Npcnih homozygous knockout mice, demonstrating increased survival, reduction of cholesterol storage, and delayed neurodegeneration. The viral vector system, including specific promoters and AAV capsid serotypes, enables efficient therapeutic gene delivery for treating or preventing cholesterol storage diseases caused by NPC1 or NPC2 dysfunction.
Claims Coverage
The patent contains two independent claims focusing on methods for treating cholesterol storage diseases, notably NPC, using viral vectors carrying NPC1 transgenes under specific promoter control. The coverage emphasizes the inventive features of vector design, promoter choice, viral serotype, and dosage.
AAV vector comprising miniEF1α promoter controlling NPC1 gene expression
The vector includes an AAV viral genome with exactly 130 base pair AAV2 inverted terminal repeats flanking a mini-elongation factor 1 alpha (miniEF1α) promoter operably linked to an NPC1 gene sequence and a rabbit beta globin poly A signal, comprising no more than 4.7 kilobases total.
Use of AAV serotype capsids for vector encapsidation
The viral vector is encapsidated with pharmaceutically acceptable carriers and specific AAV capsid serotypes selected from AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh8, AAVrh10, AAVrh33, AAV rh34, AAV Anc80, or AAV PHP.B to facilitate delivery.
Administration method for treating diseases caused by NPC1 mutation or malfunction
The method involves administering a therapeutically effective amount of the described viral vector composition to a subject having or at risk for a cholesterol storage disease caused by NPC1 mutation or malfunction, thereby treating or preventing the disease.
The claims cover methods of treatment using AAV vectors containing NPC1 under control of a miniEF1α promoter and specific viral capsids, focusing on compositions and administration methods for therapeutic delivery to treat NPC caused by NPC1 defects.
Stated Advantages
Effective treatment and prevention of Niemann-Pick disease, type C, through gene therapy utilizing viral vectors to restore NPC1 function.
Capability of crossing the blood-brain barrier and targeting neuronal tissues for therapeutic gene expression.
Increased survival and amelioration of disease symptoms demonstrated in preclinical animal models.
Documented Applications
Treatment or prevention of cholesterol storage diseases or disorders, including Niemann-Pick disease, type C, using viral gene therapy constructs encoding NPC1 or NPC2.
Gene therapy delivery via direct parenchymal brain injection, intrathecal injection, or systemic administration for CNS-targeted expression.
Therapeutic applications in human patients and animal models such as Npc1 knockout mice for neurological and hepatic symptoms of NPC.
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