Abstract

The goal is to develop gene therapies in neonates and/or infants and toddlers.
The aims are 1. determine the safety and efficacy of AAV vector, gene therapy in cystic fibrosis(CF) patients; and 2. to develop CF gene therapy applied early in life to avoid the progressive destruction of the airways. The primary focus is on CF. Project I: """"""""Adeno-associated virus vectors (AAV) for CF gene therapy"""""""" will address the issues of safety of gene therapy using AAV vectors.
The aims will be to: assess the efficiency and distribution of vector DNA transfer and to determine if repeated applications will cause any immunologic reactions, alterations in pulmonary function, or spread in distant organs in monkeys. This will be followed by a phase I clinical trial in adult CF patients. Project II: """"""""Neonatal gene therapy with AAV"""""""" investigates the consequences of early (fetal and neonatal) administration of AAV"""""""" investigates the consequences of early (fetal and neonatal) administration of AAV vectors.
Aims are to determine whether more progenitor and/or dividing cells are present in the developing airway, which cells are targeted by the vector, the lasting effect of vector administration and the effects on airway development. CF Pilot Project I will evaluate the specificity of site specific integration of wild-type and recombinant AAV vectors. It is known that wild-type AAV virus integrates into chromosome 91. Finally, there will be an Expression/ Tissue Culture Core, a Vector Core, a Clinical Core and an Administration Core.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051811-02
Application #
2228763
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S3))
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Guggino, William B; Benson, Janet; Seagrave, JeanClare et al. (2017) A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System. Hum Gene Ther Clin Dev 28:145-156
Schuster, Benjamin S; Allan, Daniel B; Kays, Joshua C et al. (2017) Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales. J Control Release 260:124-133
Schneider, Craig S; Xu, Qingguo; Boylan, Nicholas J et al. (2017) Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci Adv 3:e1601556
Kates, Max; Date, Abhijit; Yoshida, Takahiro et al. (2017) Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res 23:6592-6601
Duncan, Gregg A; Jung, James; Joseph, Andrea et al. (2016) Microstructural alterations of sputum in cystic fibrosis lung disease. JCI Insight 1:e88198
Yu, Tao; Chisholm, Jane; Choi, Woo Jin et al. (2016) Mucus-Penetrating Nanosuspensions for Enhanced Delivery of Poorly Soluble Drugs to Mucosal Surfaces. Adv Healthc Mater 5:2745-2750
Schuster, Benjamin S; Ensign, Laura M; Allan, Daniel B et al. (2015) Particle tracking in drug and gene delivery research: State-of-the-art applications and methods. Adv Drug Deliv Rev 91:70-91
Mastorakos, Panagiotis; da Silva, Adriana L; Chisholm, Jane et al. (2015) Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A 112:8720-5
Suk, Jung Soo; Kim, Anthony J; Trehan, Kanika et al. (2014) Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier. J Control Release 178:8-17
Smith, Laura J; Ul-Hasan, Taihra; Carvaines, Sarah K et al. (2014) Gene transfer properties and structural modeling of human stem cell-derived AAV. Mol Ther 22:1625-34

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