422. Selection and Optimization of Lentiviral Vector for Airway Gene Transfer in a Porcine Model of Cystic Fibrosis

For achieving retrograde gene transfer, we have so far developed two types of lentiviral vectors pseudotyped with fusion envelope glycoprotein, termed HiRet vector and NeuRet vector, consisting of distinct combinations of rabies virus and vesicular stomatitis virus glycoproteins. In the present study, we compared the patterns of retrograde transgene expression for the HiRet vs. NeuRet vectors by testing the cortical input system. These vectors were injected into the motor cortex in rats, marmosets, and macaques, and the distributions of retrograde labels were investigated in the cortex and thalamus. Our histological analysis revealed that the NeuRet vector generally exhibits a higher efficiency of retrograde gene transfer than the HiRet vector, though its capacity of retrograde transgene expression in the macaque brain is unexpectedly low, especially in terms of the intracortical connections, as compared to the rat and marmoset brains. It was also demonstrated that the NeuRet but not the HiRet vector displays sufficiently high neuron specificity and causes no marked inflammatory/immune responses at the vector injection sites in the primate (marmoset and macaque) brains. The present results indicate that the retrograde transgene efficiency of the NeuRet vector varies depending not only on the species but also on the input projections.

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904. CFTR Promoter in Lentiviral Vector System for Cystic Fibrosis Gene Therapy

Molecular Therapy ◽

10.1016/s1525-0016(16)40307-2 ◽

2008 ◽

Vol 16 ◽

pp. S337

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Lentiviral Vector ◽

Vector System ◽

Cystic Fibrosis Gene

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High lysosomal activities in cystic fibrosis tracheal gland cells corrected by adenovirus-mediated CFTR gene transfer

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/s0925-4439(98)00084-2 ◽

1999 ◽

Vol 1453 (1) ◽

pp. 14-22 ◽

Cited By ~ 4

Author(s):

W. Kammouni ◽

D. Naı̈mi ◽

W. Renaud ◽

N. Bianco ◽

C. Figarella ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Transfer ◽

Cftr Gene ◽

Gland Cells

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Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans

Nature ◽

10.1038/371802a0 ◽

1994 ◽

Vol 371 (6500) ◽

pp. 802-806 ◽

Cited By ~ 261

Author(s):

Barbara R. Grubb ◽

Raymond J. Pickles ◽

Hong Ye ◽

James R. Yankaskas ◽

Ralph N. Vick ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Transfer ◽

Adenovirus Vector ◽

Airway Epithelia ◽

Cystic Fibrosis Airway

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711. Development of a Clinically-Acceptable Lentiviral Vector for Cystic Fibrosis Airway Gene Therapy

Molecular Therapy ◽

10.1016/s1525-0016(16)33519-5 ◽

2016 ◽

Vol 24 ◽

pp. S280-S281

Author(s):

Alexandra McCarron ◽

Chantelle McIntyre ◽

Martin Donnelley ◽

Patricia Cmielewski ◽

David Parsons

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Lentiviral Vector ◽

Cystic Fibrosis Airway

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Abstract 2103: Prevention of Pulmonary Hypertension by ACE2 Gene Transfer to Lungs

Circulation ◽

10.1161/circ.116.suppl_16.ii_456-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Yoriko Yamazato ◽

KwonHo Hong ◽

Dae Song Jang ◽

Anderson J Ferreira ◽

Masanobu Yamazato ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Gene Transfer ◽

Wall Thickness ◽

Lentiviral Vector ◽

Therapeutic Potential ◽

Systolic Pressure ◽

Vector Particle ◽

Mrna Levels ◽

Alveolar Cells ◽

Ace2 Gene

Pulmonary hypertension (PH) is characterized by increase in pulmonary vascular resistance, and narrowing and loss of pulmonary microvasculare. There is an indispensable need to develop innovative approaches for its control since PH becomes refractory to current therapies in later stages. Recent discovery of angiotensin converting enzyme 2 (ACE2), its involvement in cardiac remodeling, coupled with the limited success of ACE inhibitors in PH has led us to hypothesize that shifting the balance of renin-angiotensin system (RAS) to vasoprotective ACE2-Ang1–7- mas receptor axis would result the beneficial outcome in PH. We tested this hypothesis with the use of ACE2 overexpression in lungs by lentiviral vector-mediated gene transfer. Lentiviral vector particle(3x10^8 TU) containing murine ACE2 (letni-ACE2) were injected into 6 weeks old C57BL/6 mice prior to induction of PH by administration of weekly 600 mg/kg of monocrotaline (MCT) for 8 weeks for prevention studies. In addition, lenti-ACE2 was delivered following 6 weeks MCT treatment in reversal studies. Right ventricle systolic pressure (RVSP), Real-time RT-PCR, immunohisitochemistory of ACE2 and Ang (1–7) and histology of lungs in control and lent-ACE2 treated mice were carried out to evaluated the outcome on PH. Delivery of lenti-ACE2 resulted in a long-term increase in ACE2 expression in the lungs. A 60% and 100 % increases in protein and mRNA levels for ACE2 were observed. ACE2 and Ang (1–7) immunoreactivity were observed in epithelial and alveolar cells and alveolar macrophages. MCT treatment increased in RVSP (MCT 44.5+/−5.7 mmHg, control 24+/−1.0mmHg), RV hypertrophy (RV/LV+Sp ratio; 0.31+/−0.01), and wall thickness of pulmonary vessels. ACE2 gene transfer prevented increases in RVSP (26.1+/− 1.1mmHg), and RV hypertrophy (0.26+/−0.1), and reduced vessel wall thickness. In addition, ACE2 overexpression resulted in a significant reversal of RVSP (23.5+/−0.6mmHg). Futhermore, ACE2 overexpression in mice exhibited better general appearance and gained weight compared to MCT-treated mice. ACE2 gene transfer to lungs prevents and reverses vascular remodeling and PH in MCT model of PH. These observations suggest that targeting of pulmonary ACE2 holds novel therapeutic potential for PH.

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