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.
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.


CONCLUSIONS
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.
Valles
Francisco
F
Movement Disorder Research Program, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94103, USA.
Fiandaca
Massimo S
MS
Eberling
Jamie L
JL
Starr
Philip A
PA
Larson
Paul S
PS
Christine
Chadwick W
CW
Forsayeth
John
J
Richardson
R Mark
RM
Su
Xiaomin
X
Aminoff
Michael J
MJ
Bankiewicz
Krystof S
KS
D000368:Aged; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D010300:Parkinson Disease / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy*; D049268:Positron-Emission Tomography / Q000379:methods*; D016896:Treatment Outcome
D001142:Aromatic-L-Amino-Acid Decarboxylases