Qualitative Imaging of Adeno-Associated Virus Serotype 2-Human Aromatic L-Amino Acid Decarboxylase Gene Therapy in a Phase I Study for the Treatment of Parkinson Disease

Movement Disorder Research Program, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94103, USA.
Neurosurgery (Impact Factor: 3.62). 11/2010; 67(5):1377-85. DOI: 10.1227/NEU.0b013e3181f53a5c
Source: PubMed


Putaminal convection-enhanced delivery (CED) of an adeno-associated virus serotype 2 (AAV2) vector, containing the human aromatic L-amino acid decarboxylase (hAADC) gene for the treatment of Parkinson disease (PD), has completed a phase I clinical trial.
To retrospectively analyze magnetic resonance imaging (MRI) and positron emission tomography (PET) data from the phase I trial, correlate those data with similar nonhuman primate (NHP) data, and present how such information may improve future PD gene therapy trials in preparation for the initiation of the phase II trial.
Ten patients with PD had been treated with bilateral MRI-guided putaminal infusions of AAV2-hAADC. MRI and PET scans were obtained at baseline (before vector administration) and at various intervals after treatment. Three normal adult NHPs received similar infusions into the thalamus. Imaging studies for both groups are presented, as well as hAADC immunohistochemistry for the NHPs.
Early post-CED MRI confirmed the stereotactic targeting accuracy and revealed T2 hyperintensity around the distal cannula tracts, best seen within 4 hours of surgery. Coregistration of post-CED MRI and PET scans revealed increased PET uptake at the sites of T2 hyperintensity. Similar T2 hyperintensities in NHP MRI correlated with hAADC immunohistochemistry.
Our analysis confirms the correct targeting of the CED cannula tracts within the target human putamen. Coregistration of MRI and PET confirms colocalization of T2 hyperintensities and increased PET uptake around the distal cannula tracts. Because PET uptake closely correlates with hAADC transgene expression and NHP data confirm this relationship between T2 hyperintensity and hAADC immunohistochemistry, we believe that T2-weighted MRI allows visualization of a significant part of the distribution volume of the hAADC gene therapy. Recommendations for future protocols based on these data are presented.

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    • "CED achieves high concentrations of drug with minimal off-target exposure since it bypasses the blood-brain barrier and displaces the interstitial fluid, thus making it possible to deliver large macromolecules with pinpoint accuracy. These technologies should help overcome the poor drug distributions observed in several recent high-profile clinical trials involving direct delivery of neurotrophic factors [6], [7] or gene therapy vectors for the treatment of Parkinson’s disease [8], [9] and of immunotoxins [10], [11] or chemotherapies [12] for treating brain tumors. "
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    ABSTRACT: This study presents a computational tool for auto-segmenting the distribution of brain infusions observed by magnetic resonance imaging. Clinical usage of direct infusion is increasing as physicians recognize the need to attain high drug concentrations in the target structure with minimal off-target exposure. By co-infusing a Gadolinium-based contrast agent and visualizing the distribution using real-time using magnetic resonance imaging, physicians can make informed decisions about when to stop or adjust the infusion. However, manual segmentation of the images is tedious and affected by subjective preferences for window levels, image interpolation and personal biases about where to delineate the edge of the sloped shoulder of the infusion. This study presents a computational technique that uses a Gaussian Mixture Model to efficiently classify pixels as belonging to either the high-intensity infusate or low-intensity background. The algorithm was implemented as a distributable plug-in for the widely used imaging platform OsiriX®. Four independent operators segmented fourteen anonymized datasets to validate the tool's performance. The datasets were intra-operative magnetic resonance images of infusions into the thalamus or putamen of non-human primates. The tool effectively reproduced the manual segmentation volumes, while significantly reducing intra-operator variability by 67±18%. The tool will be used to increase efficiency and reduce variability in upcoming clinical trials in neuro-oncology and gene therapy.
    PLoS ONE 06/2013; 8(6):e64452. DOI:10.1371/journal.pone.0064452 · 3.23 Impact Factor
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    • "As a result, the quality of infusions is highly variable and the effective coverage observed pre-clinically [1], [2] has been poorly reproduced in clinical trials of glial-derived neurotrophic factor (GDNF) for treating Parkinson’s disease [3] neurturin gene for treating Parkinson’s disease [4], the immunotoxin cintredekin besudotox [5],[6] for treating brain tumors or the chemotherapeutic paclitaxel [7], also for treating brain tumors. Subsequent analyses of these trials have attributed the failure to poor distribution of the delivered agents resulting from variability in the infusion techniques [5], [8], [9]. For example, the two patients with autopsy data in the neurturin trial had drug infused in less than 20% of the targeted putamen. "
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    ABSTRACT: Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials.
    PLoS ONE 02/2013; 8(2):e56397. DOI:10.1371/journal.pone.0056397 · 3.23 Impact Factor
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    • "Many considerations must be made in regard to efficiency, coverage, and catheters utilization when considering a human clinical trial with multiple stacked infusions.35,44–46 In phase I of clinical trial, employing CED of AAV2 vector into the putamen resulted consistently as in NHP experiments.74 MRI scans confirmed the precise target of CED cannula tracts, the colocalization of T2 hyperintensities and increased PET uptake around distal cannula tracts, and the relationship between T2 hyperintensity and hAACD immunohistochemistry. Bartus75 followed this study with a 2011 phase II human clinical trial focusing on direct infusions of therapeutics into the SN. "
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    ABSTRACT: The existing treatment of Parkinson's disease (PD) is directed towards substituting dopamine loss with either dopamine replacement therapy or pharmacological therapies aimed at increasing dopamine at the synapse level. Emerging viable alternatives include the use of cell-based and gene-based therapeutics. In this review, we discuss efforts in developing in vitro and in vivo models and their translation to human clinical trials for gene-based therapy of this distressing and prevalent neurodegenerative disorder. Given the mismatch between expectations from preclinical data and results of human pivotal trials, drug delivery has been identified as the key emerging area for translational research due to limitation of limited efficacy. The chief highlights of the current topic include use of improved delivery methods of gene-based therapeutic agents. Convection-enhanced delivery (CED), an advanced infusion technique with demonstrated utility in ex vivo and in vivo animal models has recently been adopted for PD gene-based therapy trials. Several preclinical studies suggest that magnetic resonance imaging (MRI)-guided navigation for accurately targeting and real time monitoring viral vector delivery (rCED) in future clinical trials involving detection of gene expression and restoration of dopaminergic function loss using pro-drug approach will greatly enhance these PD treatments.
    Annals of Neurosciences 07/2012; 19(3):133-146. DOI:10.5214/ans.0972.7531.190310
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