Using Mucosal Tissue to Evaluate Effectiveness. Charlene S. Dezzutti, Ph.D. University of Pittsburgh MTN Annual Meeting March 16, 2010
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1 Using Mucosal Tissue to Evaluate Effectiveness Charlene S. Dezzutti, Ph.D. University of Pittsburgh MTN Annual Meeting March 16, 2010
2 Drug development pathway Stage 1 Drug discovery Stage 2 Pre-clinical Stage 3 Clinical trials Stage 4 Regulatory review 10,000 compounds First clinical trial application submitted Phase I (safety) Phase II 5 compounds Phase III (efficacy) compounds people people people 1 Marketing application submitted approved drug 6.5 years 7 years 1.5 years Adapted from: Pharmaceutical Research and Manufacturers of America, 2006
3 What we ll talk about Pre-clinical microbicide testing Tissues used for explant cultures What can we do with tissue explants? Moving toward validation
4 Pre-clinical testing Traditionally done by testing the compound for anti-hiv activity and cellular toxicity Primary immune cells or cell lines for high throughput testing Handful of laboratories using mucosal tissue explant cultures
5 Why use mucosal tissues? Mucosal tissue is where the virus enters and where the product will be applied Tissue consists of relevant cell types (HIV targets) in biologically appropriate ratios Surgical remainders do not require patient recruitment obtained within a few hours of surgery Endoscopic/colposcopic biopsy require patient recruitment obtained within minutes of scoping and convenient
6 What tissues are used? Colorectal Endocervix Endometrium I. McGowan Biologicals 34:201, 2006 Ectocervix Vagina Penis (glans, foreskin) Anus
7 Colorectal and ectocervical models Colorectal tissue obtained from surgical resections or endoscopic biopsies Non-polarized (Anton/McGowan, Shattock) Polarized (Dezzutti) Ectocervical tissue obtained from premenopausal women undergoing hysterectomies Non-polarized (Asin, Shattock) Polarized (Dezzutti, Gupta [with T cell co-culture])
8 Non-polarized colorectal explants Viral exposure Culture Tissue explants (2-3mm) Media soaked gelfoam raft Media 2 mm piece of colorectal tissue Explants exposed to virus/microbicide while submerged in media (96 well plate) Explant placed on a media-soaked gelfoam raft in a 24-well plate following viral exposure Cultured in DMEM/pen/strep/±10% FCS Infection determined by presence of p24 in culture supernatants (10-14 days post exposure) Fletcher, P.S. AIDS 20:1237, 2006
9 Non-polarized colorectal explants Endoscopic biopsies + Absorbable gelatin sponge Fletcher, P.S. AIDS 20:1237, 2006
10 Polarized colorectal explants Matrigel Explant Gelfoam 1 ml medium 5 mm circular piece of colon (biopsy punch) and muscle is excised Explant is placed (epithelium on top) on presoaked gelfoam inserted into a transwell Explant is sealed with Matrigel around the epithelium Abner, S. J. Infect. Dis. 192:1545, 2005
11 Polarized colorectal explants
12 Non-polarized ectocervical explants Human cervical tissue: cut into 2-3mm explants (complete RPMI) Submerged tissue exposed to virus (2h) Wash Culture overnight Transfer explants to fresh plates Culture for days to determine infection of explants (p24 in culture supernatant) Greenhead, P. J. Virol 74:5577, 2000
13 Polarized ectocervical explants Matrigel Epithelium Stroma 1 ml DMEM 5 mm circular piece of ectocervix (biopsy punch) and muscle excised Explant inserted through a hole in filter of a transwell insert and sealed with Matrigel around the epithelium Cummins, J.E. Antimicrob Agents Chemother 51:1770, 2007
14 Polarized ectocervical explants
15 Non-polarized vs. polarized Non-polarized Pros Cons Utilize all tissue Perform more replicates Models worst case scenario Can not evaluate transmission events Can not evaluate formulations Polarized Pros Cons Biologically relevant Allows apical application of product/virus Model topical and systemic application Limits tissue utilization Limited replicates
16 What can we do with explants? Evaluate drug and/or formulation safety MTT assay Histology Drug permeability Determine product efficacy Ex vivo product testing
17 Product safety formulated Microbicide MTT assay (mitochondrial activity) Histology
18 Product safety formulated 250 MTT assay % Viability of Control Tissue Vehicle Vehicle TFV 1% Control TFV 1% Control Ectocervical Colorectal N9 Rohan, L.C., et al. PLoS ONE 5(2): e
19 Product safety formulated Histology Control TFV 1% Vehicle Control N9 Colorectal Ectocervical 3 of 5 tissues exhibited facture or sloughing of the epithelium Rohan, L.C., et al. PLoS ONE 5(2): e
20 What can we do with explants? Evaluate drug and/or formulation safety MTT assay Histology Drug permeability Determine product efficacy Ex vivo product testing
21 Drug permeability Tissue is placed between donor and receptor chambers Product is added to donor chamber Receptor chamber is sampled at designated time points
22 TFV permeability Cumulative amount of TFV in the receptor (µg) Tissue 1 Tissue 2 Tissue 3 Tissue 4 Tissue Time (min) Rohan, L.C., et al. PLoS ONE 5(2): e
23 What can we do with explants? Evaluate drug and/or formulation safety MTT assay Histology Drug permeability Determine product efficacy Ex vivo product testing
24 Product efficacy unformulated Microbicide or API HIV HIV p24 ELISA Immunohistochemistry for p24 at study endpoint ectocervix only
25 Product efficacy Topical application Systemic application HIV-1 p24gag (pg/ml) HIV-1 p24gag (pg/ml) Day of Culture Cvx, topical HIV-1 only TFV 1% Vehicle control HIV-1 only 0 min HIV-1 only TFV Day of Culture Cvx, systemic HIV-1 only 15 min Pre Rohan, L.C., et al. PLoS ONE 5(2): e
26 Product efficacy In the presence of semen Model coital independent product use
27 Testing with semen ph Osmolality mmol/kg Viscosity (cps) 100% semen % semen* % semen* % TFV gel *diluted in DMEM
28 Testing with semen MTT assay Colorectal explants Ectocervical explants %Viability of Control % semen 50% semen N9 100% semen 50% semen N9 Dezzutti Lab, unpublished data
29 Testing with semen Histology Control 100% semen 50% semen N9 Ectocervix Colorectal Dezzutti Lab, unpublished data
30 Testing with semen Permeability of 3 H-H 2 0 in Excised Human Tissue 3 H+Semen Control 3 H+DMEM CPM Time (min) Rohan Lab, unpublished data
31 Testing with semen No detectable semen enhancing viral infectivity (SEVI) effect Ectocervix 10 4 HIV-1 p24gag (pg/ml) Day of Culture 5x10 2 5x semen 5x10 3 5x semen 5x10 4 5x semen Dezzutti Lab, unpublished data
32 Testing with semen 10 4 Ectocervix HIV-1 p24 (pg/ml) HIV-1 HIV-1 + semen TFV gel TFV gel + semen Day of Culture Dezzutti Lab, unpublished data
33 Coital independent use Gel is applied for 1 h, 24 h before (pre) or after (post) exposure to HIV h pre-dosing h post-dosing HIV-1 p24gag (pg/ml) HIV-1 HIV-1 + semen TFV gel TFV gel + semen HIV-1 p24gag (pg/ml) HIV-1 HIV-1 + semen TFV gel TFV gel + semen Day of Culture Day of Culture 2 of 10 explants not protected regardless of semen 4 of 18 explants not protected regardless of semen Dezzutti Lab, unpublished data
34 What can we do with explants? Evaluate drug and/or formulation safety MTT assay Histology Drug permeability Determine product efficacy Ex vivo product testing
35 Ex vivo testing HEC Placebo UC % UC % Cumulative p24 (pg/ml) at Day V2 V2 V3 Visit V3 Visit Anton, P., McGowan, I. Poster CROI V2 V2 (ID=410) V3 Visit V3 Visit V2 V2 V3 Visit V3 Visit 10 cm 30 cm V2: Baseline; V3: 30 minutes post single dose
36 Ex vivo testing Non-polarized vs. polarized explants Median p24 (pg/ml) Day of Culture Polarized Non polarized IHC positive: 88% non-polarized 71% polarized Lynam, JD, Poster M2010
37 Explants can be used to Evaluate microbicide safety and efficacy Drug permeability In the presence of semen Multiple formulation types (gel, film, ring) Determine ex vivo efficacy Surrogate for clinical efficacy?
38 Caveats of using explants Expensive and cumbersome to obtain Independent of hormonal control Inability to regenerate/repair No vascularization No recruitment of immune cells Therefore, explants should be used for the most promising candidates (not for screening) as part of a comprehensive testing algorithm
39 MTN pre-clinical algorithm Formulated Product Formulation Testing In vitro Testing Ex vivo Testing Cervical/colorectal tissue Osmolality, ph, viscosity, in vitro release Dose Range Cell lines Lactobacillus HIV efficacy ± human secretion Absorption, permeability, and safety HIV efficacy ± human secretion Human Studies
40 Preclinical testing picture Primary cells Viral clades Mucosal Vaginal Biomarkers secretions Cell lines flora Animal Explants models
41 Acknowledgements University of Pittsburgh/Magee- Womens Research Institute Charlene Dezzutti Nicole Billitto JD Lynam Julie Russo Kevin Uranker Pam Kunjara Lisa Rohan Phillip Graebing Lin Wang Lyn Cost Bernard Moncla Kara Pryke Pitt/MWRI Ian McGowan St Georges Hospital, London Patricia Fletcher Funding Microbicide Trials Network (NIAID/NIMH/NICHD)
42 Thank you
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