Triple Transduction with Adeno-Associated Virus Vectors Expressing Tyrosine Hydroxylase, Aromatic-L-Amino-Acid Decarboxylase, and GTP Cyclohydrolase I for Gene Therapy of Parkinson's Disease
Summary Based on the hypothesis that catecholamine decreases may cause increases in biopterin, we measured the GTP cyclohydrolase I(GTPCH-I) activity and biopterin content in the cerebral cortex, midbrain/diencephalon, cerebeilum, pons/medulla oblongata, striatum , and hippocampus of brains from rats given NSDlOIS, an inhibitor for aromatic amino acid decarboxylase . The catecholamine contents decreased in all the regions tested. The changes in the GTPCH -I activity and bioptcrin content were different among the regions; they decreased in some regions contrary to expectations and increased in other regions. However, either the enzyme activity or biopterin content increased in the midbrain/ diencephalon and pons/ medulla oblongata, in which similar levels of catecholamines, GTPCH -I activity and biopterin were detected. These results suggest that for the midbrain/diencephalon and pons/medulla oblongata the surmise that a decrease in catecholamines causes an increase in the biopterin synthesis may be correct.
Abstract
BACKGROUND:
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.
OBJECTIVE:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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.
Multicistronic Lentiviral Vector-Mediated Striatal Gene Transfer of Aromatic l-Amino Acid Decarboxylase, Tyrosine Hydroxylase, and GTP Cyclohydrolase I Induces Sustained Transgene Expression, Dopamine Production, and Functional Improvement in a Rat Model of Parkinson's Disease.