Safety and tolerability of putaminal
            <i>AADC</i>
            gene therapy for Parkinson disease

Christine, Chadwick W.; Starr, Philip A.; Larson, Paul; Eberling, Jamie L.; Jagust, William J.; Hawkins, Richard A.; VanBrocklin, Henry F.; Wright, J. Fraser; Bankiewicz, Krystof S.; Aminoff, Michael J.

doi:10.1212/wnl.0b013e3181c29356

Cited by 391 publications

(324 citation statements)

References 19 publications

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“…Clinically, AAV2 has been regarded as the vector of choice for CNS gene delivery for several reasons, including its relatively widespread use in neurological gene therapy in Parkinson's disease (Kaplitt et al, 2007;Eberling et al, 2008;Marks et al, 2008;Christine et al, 2009), its tropism for neurons (Bartlett et al, 1998), and long-term CNS expression after delivery Daadi et al, 2006). Consistent with previous observations, we have also demonstrated high efficiency and cellular tropism of AAV2 for neurons after CED, with no astrogliosis (Fig.…”

Section: Aguilar Salegio Et Alsupporting

confidence: 90%

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

et al. 2010

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Gene replacement therapy for the neurological deficits caused by lysosomal storage disorders, such as in Niemann-Pick disease type A, will require widespread expression of efficacious levels of acid sphingomyelinase (ASM) in the infant human brain. At present there is no treatment available for this devastating pediatric condition. This is partly because of inherent constraints associated with the efficient delivery of therapeutic agents into the CNS of higher order models. In this study we used an adeno-associated virus type 2 (AAV2) vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA) to transduce highly interconnected CNS regions such as the brainstem and thalamus. On the basis of our data showing global cortical expression of a secreted reporter after thalamic delivery in nonhuman primates (NHPs), we set out to investigate whether such widespread expression could be enhanced after brainstem infusion. To maximize delivery of the therapeutic transgene throughout the CNS, we combined a single brainstem infusion with bilateral thalamic infusions in naive NHPs. We found that enzymatic augmentation in brainstem, thalamic, cortical, as well subcortical areas provided convincing evidence that much of the large NHP brain can be transduced with as few as three injection sites.

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Section: Aguilar Salegio Et Alsupporting

confidence: 90%

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

et al. 2010

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“…A phase I clinical trial, started in 2005 in five patients who received bilateral intrastriatal vector administration, showed only modest efficacy in 'off' state 6 months post transfection. In a second cohort of patients, who received a higher concentration of vector, there was also no significant improvement in the UPDRS rating scale despite increased 18 F-fluoro-l-m-tyrosine binding in PET studies (Christine et al, 2009).…”

Section: Viral Vector-mediated Striatal Dopamine Replacementmentioning

confidence: 85%

“…Studies have aimed at two main anatomical targets, the STN, in which an AAV vector has been used to deliver the enzyme glutamic acid decarboxylase (GAD) with the hope of transforming some glutamatergic STN neurons into GABAreleasing cells (Kaplitt et al, 2007;Lewitt et al, 2011), and the striatum, in which AAV or lentiviral vectors are used to generate striatal neurons that produce dopamine either by themselves or from dietary tyrosine or LD administered as a drug (Eberling et al, 2008;Christine et al, 2009;Jarraya et al, 2009). Ongoing trials are in progress to assess the efficacy of these approaches in advanced PD patients.…”

Section: Gene Therapy For Pdmentioning

confidence: 99%

“…The lack of these basic features may potentially prove harmful to striatal neurons because of an overproduction of cytosolic dopamine, which may lead to oxidative stress in transfected cells (Chen et al, 2008), and the possibility that non-regulated release of dopamine by striatal neurons aggravates dyskinesias, as seen in MPTP-treated monkeys (Bankiewicz et al, 2006a, b) and some patients enrolled in the safety trial (Christine et al, 2009). Thus, a third approach being considered that could overcome these problems is a continuous LD delivery strategy, achieved by delivery of TH and GTP cyclohydrolase 1 (a key co-factor needed for TH function), resulting in LD production without interference with endogenous AADC, and without the production of the potentially toxic dopamine.…”

Section: Viral Vector-mediated Striatal Dopamine Replacementmentioning

confidence: 99%

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Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…CED of AAV2-hAADC results in robust, essentially permanent, gene expression in the striatum and its beneficial effect has been demonstrated in several preclinical studies in rodent and nonhuman primate (NHP) models of PD (Bankiewicz et al, 2000(Bankiewicz et al, , 2006SanchezPernaute et al, 2001;Forsayeth et al, 2006;Hadaczek et al, 2010). These preclinical studies led to a phase I clinical trial in patients with PD (Eberling et al, 2008;Christine et al, 2009;Valles et al, 2010), in which two cohorts of patients with moderately advanced PD received a bilateral infusion of either a low or high dose of AAV2-hAADC vector into the putamen. Although patients showed apparent improvement in terms of Unified Parkinson's Disease Rating Scale (UPDRS) scores and reductions in antiparkinsonian medications, such improvement was modest compared with the results previously reported in parkinsonian NHP (Bankiewicz et al, 2006).…”

mentioning

confidence: 99%

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

et al. 2012

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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]-a-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.

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Safety and tolerability of putaminal AADC gene therapy for Parkinson disease

Abstract: Background:In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over

Cited by 391 publications

References 19 publications

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

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