Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC

Bankiewicz, Krystof S.; Forsayeth, John; Eberling, Jamie L.; Sánchez‐Pernaute, Rosario; Pivirotto, Philip; Bringas, John; Herscovitch, Peter; Carson, Richard E.; Eckelman, William C.; Reutter, B.W.; Cunningham, Janet

doi:10.1016/j.ymthe.2006.05.005

Cited by 252 publications

(179 citation statements)

References 29 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…To address these limitations, we have recently assessed the usefulness of adeno-associated virus serotype 4 (AAV-4), an ependymotrophic vector that expresses in a sustained fashion, and is relatively nonimmunogenic. Indeed, AAV has been shown to support expression for as much as 15 months in the mouse brain [146], 19 months in the rat brain [147], and for more than 6 years in the primate brain [148]. On that basis, we used intraventricular injections of AAV-4, which selectively transduce the ependymal cells of the ventricular wall to deliver BDNF and Noggin to the ependymal layer, which lies in close proximity to the adjacent subependymal cell population.…”

Section: Induced Neuronal Addition As a Treatment For Huntington's DImentioning

confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

View full text Add to dashboard Cite

Section: Induced Neuronal Addition As a Treatment For Huntington's DImentioning

confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

View full text Add to dashboard Cite

“…[7][8][9][10][11][12] Among them, AAV vectors are of particular interest because they are non-pathogenic, can transduce non-dividing cells and result in longterm transgene expression. 13,14 They also cause no detected toxicity and minimal immune responses in transduced regions. 15,16 Moreover, AAV vectors are FDA (Food and Drug Administration) approved and are currently being used in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Zhao

et al. 2009

Gene Ther

View full text Add to dashboard Cite

We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adenoassociated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.

show abstract

“…Various AAV serotypes have been proposed in different animal models to treat diseases by gene therapy (Halbert et al, 2001;Dodge et al, 2005;Bankiewicz et al, 2006;Inagaki et al, 2006;Tas et al, 2006). The most frequently used serotype in neurological clinical studies has been AAV2 (Fiandaca et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

Hadaczek¹,

Forsayeth²,

Mirek³

et al. 2008

Human Gene Therapy

Self Cite

View full text Add to dashboard Cite

We used convection-enhanced delivery (CED) to characterize gene delivery mediated by adeno-associated virus type 1 (AAV1) by tracking expression of hrGFP (humanized green fluorescent protein from Renilla reniformis) into the striatum, basal forebrain, and corona radiata of monkey brain. Four cynomolgus monkeys received single infusions into corona radiata, putamen, and caudate. The other group (n ¼ 4) received infusions into basal forebrain. Thirty days after infusion animals were killed and their brains were processed for immunohistochemical evaluation. Volumetric analysis of GFP-positive brain areas was performed. AAV1-hrGFP infusions resulted in approximately 550, 700, and 73 mm 3 coverage after infusion into corona radiata, striatum, and basal forebrain, respectively. Aside from targeted regions, other brain structures also showed GFP signal (internal and external globus pallidus, subthalamic nucleus), supporting the idea that AAV1 is actively trafficked to regions distal from the infusion site. In addition to neuronal transduction, a significant nonneuronal cell population was transduced by AAV1 vector; for example, oligodendrocytes in corona radiata and astrocytes in the striatum. We observed a strong humoral and cell-mediated response against AAV1-hrGFP in transduced monkeys irrespective of the anatomic location of the infusion, as evidenced by induction of circulating anti-AAV1 and anti-hrGFP antibodies, as well as infiltration of CD4 + lymphocytes and upregulation of MHC-II in regions infused with vector. We conclude that transduction of antigen-presenting cells within the CNS is a likely cause of this response and that caution is warranted when foreign transgenes are used as reporters in gene therapy studies with vectors with broader tropism than AAV2.

show abstract

Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC

Cited by 252 publications

References 29 publications

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

Contact Info

Product

Resources

About