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

ArticleinNeurosurgery 67(5):1377-85 · November 2010with33 Reads
DOI: 10.1227/NEU.0b013e3181f53a5c · Source: PubMed
Abstract
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.
    • "With the MPTP hemiparkinsonian NHP model (Bankiewicz et al., 1986; Eberling et al., 1998) there is also the opportunity to quantitate effective DA-ergic discrepancies between the two brain hemispheres, through quantifying drug-induced rotation, as has been utilized historically in rats (Mendez et al., 1975; Ungerstedt and Arbuthnott, 1970 ) to document extent of DA-ergic striatal denervation and treatment efficacy (Björklund et al., 1987). Anatomic and functional neuroimaging in the MPTP NHP model closely correlates with the human PD condition (Valles et al., 2010), without obvious anatomical discrepancies. Anatomical imaging of NHPs for stereotactic targeting is typically performed on human magnetic resonance (MR) scanners, allows correlation to human anatomy (Fiandaca et al., 2011; Yin et al., 2009 Yin et al., , 2010 Yin et al., , 2011 ), and has been useful in preparation for human clinical PD investigations (Richardson et al., 2011aRichardson et al., , 2011b ). "
    [Show abstract] [Hide abstract] ABSTRACT: In this review, we consider the use of nonhuman primate (NHP) models of Parkinson's disease (PD) produced using viral-mediated gene delivery and information they provide in comparison to other model systems in rodents and NHPs. To date, rodent and NHP PD models have found it difficult to fully recapitulate the human disorder and, therefore, provide little actual insight into disease progression. The viral-mediated gene delivery method for α-synuclein has been shown to produce a parkinsonian rodent and NHP. This novel viral-mediated gene transfer model in the NHP appears to provide a significant advance beyond neurotoxicant models, by more closely mimicking the more chronic time course of developed behavioral deterioration and neuropathology. Although we agree that the use of these novel methods inducing parkinsonian NHPs may provide relevant treatment insights, beyond those of more standard PD models, we remain cautious as to the preclinical models' ability to predict outcomes in human trials. In specific cases of certain novel medical therapeutics, therefore, we also consider the phase 0 clinical trial as offering an alternative to the currently non-predictive preclinical models, including those in the NHP.
    Full-text · Article · Mar 2014
    • "With the MPTP hemiparkinsonian NHP model (Bankiewicz et al., 1986; Eberling et al., 1998) there is also the opportunity to quantitate effective DA-ergic discrepancies between the two brain hemispheres, through quantifying drug-induced rotation, as has been utilized historically in rats (Mendez et al., 1975; Ungerstedt and Arbuthnott, 1970 ) to document extent of DA-ergic striatal denervation and treatment efficacy (Björklund et al., 1987). Anatomic and functional neuroimaging in the MPTP NHP model closely correlates with the human PD condition (Valles et al., 2010), without obvious anatomical discrepancies. Anatomical imaging of NHPs for stereotactic targeting is typically performed on human magnetic resonance (MR) scanners, allows correlation to human anatomy (Fiandaca et al., 2011; Yin et al., 2009 Yin et al., , 2010 Yin et al., , 2011 ), and has been useful in preparation for human clinical PD investigations (Richardson et al., 2011aRichardson et al., , 2011b ). "
    [Show abstract] [Hide abstract] ABSTRACT: Export Date: 18 October 2014
    Full-text · Article · Jan 2014 · PLoS ONE
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2013
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