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1.
Hum Gene Ther ; 23(8): 891-902, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22574943

ABSTRACT

Niemann-Pick disease is a lysosomal storage disorder resulting from inherited deficiency in acid sphingomyelinase (ASM). Use of adeno-associated virus serotype 2 (AAV2) to deliver human acid sphingomyelinase (hASM) is currently being explored as a means to treat the devastating neurological features of NPD, which are refractory to traditional enzyme replacement therapy. In this study, we evaluated the long-term efficacy and safety of AAV2-hASM after direct infusion into the CNS of nonhuman primates. First, we confirmed the efficacy of AAV2-hASM in naive rats, which exhibited increased ASM expression and enzyme activity after infusion, without evidence of local or systemic toxicity. Next, the model was adapted to naive nonhuman primates (NHPs) with various doses of AAV2-hASM or saline delivered into the brainstem and both thalami. Strikingly, NHPs that received a high dose of AAV2-hASM displayed significant motor deficits that were not seen in low-dose animals in both the short-term (3-month) and long-term (9-month) treatment groups. In treated NHPs, ASM expression and activity were elevated with associated alterations in the sphingolipidomic profile in brain regions transduced with AAV2-hASM. Initial histological analysis indicated marked inflammatory reactions, and immunohistochemical analysis confirmed a robust inflammatory response. Importantly, pronounced upregulation of the chemokine CCL5, a target of ASM-mediated inflammatory signaling, was detected that correlated with the inflammatory response, providing a possible mechanism for hASM-associated toxicity. This study defines dose-dependent and dose-independent toxicities of AAV2-hASM in the naive primate brain, and reveals potential challenges in the design of a clinical trial.


Subject(s)
Brain/metabolism , Brain/pathology , Dependovirus/genetics , Sphingomyelin Phosphodiesterase/genetics , Animals , Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Genetic Therapy , Genetic Vectors , Humans , Niemann-Pick Diseases/therapy , Rats , Rats, Sprague-Dawley , Sphingomyelin Phosphodiesterase/metabolism , Up-Regulation
2.
Hum Gene Ther ; 23(2): 210-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22017504

ABSTRACT

Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-(18)F]-α-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.


Subject(s)
Corpus Striatum/enzymology , Dependovirus/genetics , Dopa Decarboxylase/genetics , Gene Transfer Techniques , Animals , Catheterization , Caudate Nucleus/enzymology , Dopa Decarboxylase/metabolism , Female , Humans , Macaca mulatta , Magnetic Resonance Imaging , Neurons/enzymology , Neurons/pathology , Putamen/enzymology , Putamen/pathology , Stereotaxic Techniques , Transgenes
3.
Hum Gene Ther ; 23(4): 382-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22201473

ABSTRACT

Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector has been reported as a good candidate for intravascular gene delivery, but low levels of preexisting antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular delivery and cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue in nonhuman primates. Both delivery routes generated similar distribution patterns, although we observed a more robust level of transduction after CSF delivery. Consistent with previous reports administering AAV9, we found greater astrocytic than neuronal tropism via both routes, although we did find a greater magnitude of CNS transduction after CSF delivery compared with intravascular delivery. Last, we have demonstrated that delivery of AAV9 into the CSF does not shield against AAV antibodies. This has obvious implications when developing and/or implementing any clinical trial studies.


Subject(s)
Brain/metabolism , Dependovirus/genetics , Genetic Vectors/administration & dosage , Transduction, Genetic , Animals , Carotid Arteries , Cisterna Magna , Female , Genetic Therapy , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Infusions, Intravenous , Macaca fascicularis , Macaca mulatta , Male , Tissue Distribution
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