RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy

Hu, Chuhong; Busuttil, Ronald W.; Lipshutz, Gerald S.

doi:10.1002/jgm.1496

Cited by 73 publications

(96 citation statements)

References 52 publications

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“…Finally, neonatal immune immaturity (particularly of B cells) may result in blunted immune responses to the vector or the transgene, and may induce B cell immune tolerance. [15][16][17] Earlier studies conducted in our laboratory demonstrated that AAV serotype rh10 led to greater maintenance of copy number in the liver 18 and led to the selection of this serotype as a gene delivery vector for these studies. Knowing that the copy number would decline rapidly following the initial neonatal injection, animals received a second injection when they reached a weight of 10 g (about day 20 of life).…”

Section: Discussionmentioning

confidence: 99%

Long-term Survival of the Juvenile Lethal Arginase-deficient Mouse With AAV Gene Therapy

Lee

Bhargava

et al. 2012

Molecular Therapy

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Arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia. Human patients suffer from neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation. In a murine model, onset of the phenotypic abnormality is heralded by weight loss beginning around day 15 with death occurring typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. The goal of this study was to address the development of a gene therapy approach for arginase deficiency beginning in the neonatal period. Lifespan extension, body weight, circulating amino acids and ammonia levels were examined as outcome parameters after gene therapy with an adeno-associated viral vector expressing arginase was administered to mice on the second day of life (DOL). One-hundred percent of untreated arginase-deficient mice died by DOL 24, whereas 89% of the adeno-associated virus (AAV)-treated arginase deficient mice have survived for >8 months. While animals at 8 months demonstrate elevated glutamine levels, ammonia is less than three times that of controls and arginine levels are normal. These studies are the first to demonstrate that AAV-based therapy for arginase deficiency is effective and supports the development of gene therapy for this and the other urea cycle disorders.

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Section: Discussionmentioning

confidence: 99%

Long-term Survival of the Juvenile Lethal Arginase-deficient Mouse With AAV Gene Therapy

Lee

Bhargava

et al. 2012

Molecular Therapy

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“…11,14 Among these new vectors, AAV-rh10 showed high efficacy to transduce neurons in adult and neonatal rodent brain. 11,[15][16][17][18] AAV-rh10-mediated transduction of other cell types has not been thoroughly examined.…”

Section: Introductionmentioning

confidence: 98%

Transduction efficiency of neurons and glial cells by AAV-1, -5, -9, -rh10 and -hu11 serotypes in rat spinal cord following contusion injury

et al. 2014

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Adeno-associated viruses (AAVs) are a promising system for therapeutic gene delivery to neurons in a number of neurodegenerative conditions including spinal cord injuries (SCIs). Considering the role of macrophages and glia in the progression of 'secondary damage', we searched for the optimal vectors for gene transfer to both neurons and glia following contusion SCI in adult rats. Contusion models share many similarities to most human spinal cord traumas. Several AAV serotypes known for their neuronal tropism expressing enhanced green-fluorescent protein (GFP) were injected intraspinally following thoracic T10 contusion. We systematically compared the transduction efficacy and cellular tropism of these vectors for neurons, macrophages/microglia, oligodendrocytes, astrocytes and NG2-positive glial cells following contusion SCI. No additional changes in inflammatory responses or behavioral performance were observed for any of the vectors. We identified that AAV-rh10 induced robust transduction of both neuronal and glial cells. Even though efficacy to transduce neurons was comparable to already established AAV-1, AAV-5 and AAV-9, AAV-rh10 transduced significantly higher number of macrophages/microglia and oligodendrocytes in damaged spinal cord compared with other serotypes tested. Thus, AAV-rh10 carries promising potential as a gene therapy vector, particularly if both the neuronal and glial cell populations in damaged spinal cord are targeted.

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“…Indeed recent studies have shown long term safety and transgene expression for over 5 years in a large cohort of non human primates systemically injected with AAV8 based vectors [34]. In addition, persistent transgene expression and safety were also shown after neonatal mice intravenous injection of AAV based vectors, including AAV8 [35]. Our studies show the potential of gene therapy to treat GNE myopathy using an AAV8 based platform.…”

Section: Discussionmentioning

confidence: 58%

Sustained expression and safety of human GNE in normal mice after gene transfer based on AAV8 systemic delivery

Mitrani-Rosenbaum

Yakovlev

Cohen

et al. 2012

Neuromuscular Disorders

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RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy

Cited by 73 publications

References 52 publications

Long-term Survival of the Juvenile Lethal Arginase-deficient Mouse With AAV Gene Therapy

Long-term Survival of the Juvenile Lethal Arginase-deficient Mouse With AAV Gene Therapy

Transduction efficiency of neurons and glial cells by AAV-1, -5, -9, -rh10 and -hu11 serotypes in rat spinal cord following contusion injury

Sustained expression and safety of human GNE in normal mice after gene transfer based on AAV8 systemic delivery

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