Gene therapy for hypertension: Antisense inhibition with adeno-associated viral vector delivery targeting angiotensin II type 1-receptor messenger ribonucleic acid

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

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17β-Hydroxysteroid Dehydrogenase Type 1 and 2 Expression in the Human Fetus1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.1.6323 ◽

2000 ◽

Vol 85 (1) ◽

pp. 410-416 ◽

Cited By ~ 1

Author(s):

Junji Takeyama ◽

Takashi Suzuki ◽

Gen Hirasawa ◽

Yasunari Muramatsu ◽

Hiroshi Nagura ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Epithelial Cells ◽

Ribonucleic Acid ◽

Estrogenic Activity ◽

Expression Patterns ◽

Hydroxysteroid Dehydrogenase ◽

Pcr Analysis ◽

Maternal Circulation ◽

Messenger Ribonucleic Acid

The present study investigates the expression patterns of 17β-hydroxysteroid dehydrogenase (17βHSD) isozymes in human fetal tissues to understand how estrogenic activity is regulated in the human fetus. Using enzyme assay, high 17βHSD activity was detected in the placenta and liver, and low levels of 17βHSD activity were also present in the gastrointestinal tract and kidney. After Northern blot analysis, we detected the messenger ribonucleic acid for 17βHSD type 1 (17βHSD1) only in the placenta, whereas that for 17βHSD type 2 (17βHSD2) was detected in the placenta, liver, gastrointestinal tract, and urinary tract at 20 gestational weeks. In RT-PCR analysis of the messenger ribonucleic acid transcripts, 17βHSD1 was predominantly expressed in the placenta, brain, heart, lung, and adrenal, whereas 17βHSD2 expression was predominantly detected in the liver, gastrointestinal tract, and kidney. In addition, we detected 17βHSD2 immunoreactive protein in surface epithelial cells of the stomach, absorptive epithelial cells of the small intestine and colon, hepatocytes of the liver, and interstitial cells surrounding the urinary tubules of the renal medulla. 17βHSD2 in these tissues may be functioning in the prevention of in utero exposure of the fetus to excessive estradiol from the maternal circulation and amniotic fluids.

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