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

Neurosurgery ◽  
2010 ◽  
Vol 67 (5) ◽  
pp. 1377-1385 ◽  
Author(s):  
Francisco Valles ◽  
Massimo S Fiandaca ◽  
Jamie L Eberling ◽  
Philip A Starr ◽  
Paul S Larson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
Parkinson Disease ◽  
Phase I ◽  
Acid Decarboxylase ◽  
Adeno Associated Virus ◽  
Amino Acid Decarboxylase ◽  
Virus Serotype ◽  
T2 Hyperintensity ◽  
Pet Scans

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.

Reduced Immunogenicity of Intraparenchymal Delivery of Adeno-Associated Virus Serotype 2 Vectors: Brief Overview

2021 ◽  
Vol 21 ◽  
Author(s):  
Wuh-Liang Hwu ◽  
Shin-Ichi Muramatsu ◽  
Bruria Gidoni-Ben-Zeev
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Acid Decarboxylase ◽  
Adeno Associated Virus ◽  
Amino Acid Decarboxylase ◽  
Virus Serotype ◽  
The Brain ◽  
Decarboxylase Deficiency

: Preexisting immunity to adeno-associated virus (AAV) poses a concern in AAV vector–mediated gene therapy. Localized administration of low doses of carefully chosen AAV serotypes can mitigate the risk of an immune response. This article will illustrate the low risk of immune response to AAV serotype 2 vector–mediated gene therapy to the brain with support from clinical trial data in aromatic L-amino acid decarboxylase deficiency and Parkinson disease.

scholarly journals A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease

2010 ◽  
Vol 18 (9) ◽  
pp. 1731-1735 ◽  
Author(s):  
Shin-ichi Muramatsu ◽  
Ken-ichi Fujimoto ◽  
Seiya Kato ◽  
Hiroaki Mizukami ◽  
Sayaka Asari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Amino Acid ◽  
Phase I ◽  
Phase I Study ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

Gene therapy improves brain white matter in aromatic l‐amino acid decarboxylase deficiency

2019 ◽  
Vol 85 (5) ◽  
pp. 644-652 ◽  
Author(s):  
Chih‐Hsien Tseng ◽  
Yin‐Hsiu Chien ◽  
Ni‐Chung Lee ◽  
Yung‐Chin Hsu ◽  
Shinn‐Forng Peng ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
White Matter ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Brain White Matter ◽  
Decarboxylase Deficiency

scholarly journals Identification and Characterization of Nuclear and Nucleolar Localization Signals in the Adeno-Associated Virus Serotype 2 Assembly-Activating Protein

2014 ◽  
Vol 89 (6) ◽  
pp. 3038-3048 ◽  
Author(s):  
Lauriel F. Earley ◽  
Yasuhiro Kawano ◽  
Kei Adachi ◽  
Xiao-Xin Sun ◽  
Mu-Shui Dai ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
Intracellular Localization ◽  
Viral Capsid ◽  
Nucleolar Localization ◽  
Capsid Assembly ◽  
Dependent Manner ◽  
Carboxy Terminus ◽  
Adeno Associated Virus ◽  
Virus Serotype

ABSTRACTAssembly-activating protein (AAP) of adeno-associated virus serotype 2 (AAV2) is a nucleolar-localizing protein that plays a critical role in transporting the viral capsid VP3 protein to the nucleolus for assembly. Here, we identify and characterize AAV2 AAP (AAP2) nuclear (NLS) and nucleolar (NoLS) localization signals near the carboxy-terminal region of AAP2 (amino acid positions 144 to 184) (AAP2144–184). This region contains five basic-amino-acid-rich (BR) clusters, KSKRSRR (AAP2BR1), RRR (AAP2BR2), RFR (AAP2BR3), RSTSSR (AAP2BR4), and RRIK (AAP2BR5), from the amino terminus to the carboxy terminus. We created 30 AAP2BR mutants by arginine/lysine-to-alanine mutagenesis or deletion of AAP2BRs and 8 and 1 green fluorescent protein (GFP)-AAP2BR and β-galactosidase–AAP2BR fusion proteins, respectively, and analyzed their intracellular localization in HeLa cells by immunofluorescence microscopy. The results showed that AAP2144–184has redundant multipartite NLSs and that any combinations of 4 AAP2BRs, but not 3 or less, can constitute a functional NLS-NoLS; AAP2BR1 and AAP2BR2 play the most influential role for nuclear localization, but either one of the two AAP2BRs is dispensable if all 4 of the other AAP2BRs are present, resulting in 3 different, overlapping NLS motifs; and the NoLS is shared redundantly among the five AAP2BRs and functions in a context-dependent manner. AAP2BR mutations not only resulted in aberrant intracellular localization, but also attenuated AAP2 protein expression to various degrees, and both of these abnormalities have a significant negative impact on capsid production. Thus, this study reveals the organization of the intermingling NLSs and NoLSs in AAP2 and provides insights into their functional roles in capsid assembly.IMPORTANCEAdeno-associated virus (AAV) has become a popular and successful vector forin vivogene therapy; however, its biology has yet to be fully understood. In this regard, the recent discovery of the assembly-activating protein (AAP), a nonstructural, nucleolar-localizing AAV protein essential for viral capsid assembly, has provided us a new opportunity to better understand the fundamental processes required for virion formation. Here, we identify clusters of basic amino acids in the carboxy terminus of AAP from AAV serotype 2 (AAV2) that act as nuclear and nucleolar localization signals. We also demonstrate their importance in maintaining AAP expression levels and efficient production of viral capsids. Insights into the functions of AAP can elucidate the requirements and process for AAV capsid assembly, which may lead to improved vector production for use in gene therapy. This study also contributes to the growing body of work on nuclear and nucleolar localization signals.

scholarly journals Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency

2012 ◽  
Vol 4 (134) ◽  
pp. 134ra61-134ra61 ◽  
Author(s):  
W.-L. Hwu ◽  
S.-i. Muramatsu ◽  
S.-H. Tseng ◽  
K.-Y. Tzen ◽  
N.-C. Lee ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Decarboxylase Deficiency
Sign in / Sign up

Export Citation Format

Share Document