A Dose-Ranging Study of AAV-hAADC Therapy in Parkinsonian Monkeys

Forsayeth, John; Eberling, Jamie L.; Sanftner, Laura; Zhu, Zhen; Pivirotto, Philip; Bringas, John; Cunningham, Janet; Bankiewicz, Krystof S.

doi:10.1016/j.ymthe.2006.04.008

Cited by 90 publications

(68 citation statements)

References 19 publications

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“…In light of findings from various in vitro preparations and rat models of PD (Azzouz et al, 2002;Bankiewicz et al, 2006a, b;Forsayeth et al, 2006;Jarraya et al, 2009), two gene therapy approaches to render striatal neurons as sources of dopamine or DOPA are currently being explored in clinical trials. In the first trial, the utility of a triple enzyme transfer is examined.…”

Section: Viral Vector-mediated Striatal Dopamine Replacementmentioning

confidence: 99%

“…In this case, active neurotransmitter production is expected only after the patients take LD, so that the magnitude of the functional effects could be adjusted by regulating the oral LD dose (Bjorklund et al, 2010b). Testing in MPTP-treated monkeys (Bankiewicz et al, 2006a, b;Forsayeth et al, 2006) showed stable long-term expression of the vector for up to 6 years, which was accompanied by improvement in clinical rating scores and a reduction of LD-associated side effects (Bankiewicz et al, 2006a, b;Forsayeth et al, 2006). 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.…”

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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Section: Viral Vector-mediated Striatal Dopamine Replacementmentioning

confidence: 99%

Section: Viral Vector-mediated Striatal Dopamine Replacementmentioning

confidence: 99%

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

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

View full text Add to dashboard Cite

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“…Animals slightly improved their parkinsonism after receiving AAV2-hAADC, because study animals were only mildly lesioned with MPTP in contrast to preclinical efficacy studies in which animals were severely overlesioned (Bankiewicz et al, 2006;Forsayeth et al, 2006). This high vector dose (7.0 · 10 11 VG) resulted in strong AADC expression in the striatum.…”

Section: Discussionmentioning

confidence: 99%

“…It was unnecessary to conduct an efficacy study of AAV2-hAADC in NHP because that has been abundantly established (Bankiewicz et al, 2006;Forsayeth et al, 2006;Hadaczek et al, 2010). These data form the basis of a proposed clinical trial of AAV2-hAADC in PD with the recognition that the delivery technique in previous phase I studies (Eberling et al, 2008;Christine et al, 2009;Muramatsu et al, 2010) was unable to ensure sufficient distribution and transgene expression to be able to achieve optimal non-rate-limiting AADC activity in transduced tissue .…”

Section: Discussionmentioning

confidence: 99%

“…CED is a pressurized parenchymal infusion technique that allows therapeutic agents to be distributed throughout large volumes of brain (Bobo et al, 1994). 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.…”

mentioning

confidence: 99%

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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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Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease

Christine

Bankiewicz

Laar

et al. 2019

Annals of Neurology

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117

159

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Objective To understand the safety, putaminal coverage, and enzyme expression of adeno‐associated viral vector serotype‐2 encoding the complementary DNA for the enzyme, aromatic L‐amino acid decarboxylase (VY‐AADC01), delivered using novel intraoperative monitoring to optimize delivery. Methods Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY‐AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 10 11 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10 11 vg); cohort 2 received the same concentration (8.3 × 10 11 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10 12 vg); and cohort 3 received 2.6 × 10 12 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10 12 vg). (18)F‐fluoro‐L‐dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. Results MRI‐guided administration of ascending VY‐AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of –15%, –33%, and –42%, respectively, at 6 months. At 12 months, there were dose‐related improvements in clinical outcomes, including increases in patient‐reported ON‐time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. Interpretation Novel intraoperative monitoring of administration facilitated targeted delivery of VY‐AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704–714

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A Dose-Ranging Study of AAV-hAADC Therapy in Parkinsonian Monkeys

Cited by 90 publications

References 19 publications

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

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

Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease

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