Sexually transmitted infections (STIs) affect 340 million new people each year worldwide, including an estimated 20 million new infections in the US, adding an estimated $17 billion to US national healthcare costs per year. This application requests renewal of a bioengineering project that began in 1990. Our overall objective is to evaluate the ability of molecules, particles, and cells to move in mucosal tissues and to use that understanding to design methods for the controlled delivery of agents to prevent STIs. During the period since our last competing application, we completed a wide-ranging series of studies designed to show the potential for controlled drug delivery systems in this setting. We showed that: 1) antibodies, DNA, RNA, and peptide nucleic acids can be released slowly from biocompatible polymers, including nanoparticles (NPs), and these agents are active at mucosal surfaces; 2) surface-modified NPs penetrate readily through unstirred human cervical mucus; 3) vaginal rings releasing protein antigens can stimulate long-lasting, mucosal immunity; 4) polymer NPs loaded with siRNA delivered to the vaginal mucosal surface are capable of knocking down genes that interfere with HSV transmission in mice; and 5) NPs loaded with siRNA directed against SIV genes reduce viral loads in chronically infected macaques. In this renewal period, we exploit the experience we have gained in past studies, by presenting a focused plan to develop a safe and effective topically-administered NP delivery system for prevention and treatment of HSV-2 infections. The proposed work builds on what we have learned over past grant periods and provides a clear route for translation of one of our most significant innovations to clinical practice. We will accomplish our goal in three specific aims: First, we will optimize multifunctional NPs for topical siRNA delivery in the female reproductive tract. The multifunctional NPs will be based on our biocompatible PLGA delivery systems with additions to improve effectiveness and safety: cationic polymers will enhance siRNA loading and endosomal escape; PEG will facilitate mucus penetration; and shedding of PEG will facilitate vaginal retention and cellular uptake. We will test efficiency, duration, and toxicity o these multifunctional NPs after vaginal administration in mice. We will also examine the toxicity of our best preparations in non-human primates. Second, we will determine the effectiveness of these multifunctional NPs for prevention of HSV-2 infections. Third, we will measure the effectiveness of these NPs for treatment of recurrent HSV-2 infections. These studies will use state-of-the-art animal models to test a new method for prevention of HSV-2 transmission and treatment of recurrence.

Public Health Relevance

Despite vigorous research and development efforts over the past decades, adequate methods to prevent the transmission of sexually transmitted infections (STIs), including infections from HSV, are not available. Here we propose to develop intravaginal delivery systems aimed at enhancing the effectiveness and safety of siRNA-based agents for prevention and treatment of HSV-2 infections. This work will lead to safer and more effective methods for women to protect themselves from new HSV infections, and treat recurrent infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000487-23
Application #
9353807
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Rampulla, David
Project Start
2002-09-04
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
23
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kudalkar, Shalley N; Beloor, Jagadish; Quijano, Elias et al. (2018) From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proc Natl Acad Sci U S A 115:E802-E811
Yockey, Laura J; Iwasaki, Akiko (2018) Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. Immunity 49:397-412
Gopinath, Smita; Kim, Myoungjoo V; Rakib, Tasfia et al. (2018) Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner. Nat Microbiol 3:611-621
Yockey, Laura J; Jurado, Kellie A; Arora, Nitin et al. (2018) Type I interferons instigate fetal demise after Zika virus infection. Sci Immunol 3:
Mohideen, Muneeb; Quijano, Elias; Song, Eric et al. (2017) Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir. Biomaterials 144:144-154
Iwasaki, Akiko (2017) Immune Regulation of Antibody Access to Neuronal Tissues. Trends Mol Med 23:227-245
Steinbach, Jill M; Seo, Young-Eun; Saltzman, W Mark (2016) Cell penetrating peptide-modified poly(lactic-co-glycolic acid) nanoparticles with enhanced cell internalization. Acta Biomater 30:49-61
Gupta, Anisha; Bahal, Raman; Gupta, Meera et al. (2016) Nanotechnology for delivery of peptide nucleic acids (PNAs). J Control Release 240:302-311
Gavrilov, Kseniya; Seo, Young-Eun; Tietjen, Gregory T et al. (2015) Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence. Proc Natl Acad Sci U S A 112:E6597-605
McNeer, Nicole Ali; Anandalingam, Kavitha; Fields, Rachel J et al. (2015) Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nat Commun 6:6952

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