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Sanjay K Jain, MD Director, Ci3R Associate Professor of Pediatrics & International Health Department of Pediatrics & Center for TB Research Johns Hopkins University Baltimore, Maryland, USA • Most experts agree that Infections will not be eradicated for decades, or maybe never . . . • Are we planning for the future, and utilizing the advances in technology that may be applicable to Infectious Diseases? • Does diagnosis and monitoring of infections in special situations (hard to get locations, difficult to grow bugs, e.g. M.tb.) merit the development and / or use of technologies, that may be different from those being developed currently? The future is not what it used to be MGIT Fundamental diagnostic: 1882 Need to isolate the bug Fundamental diagnostic: 2013 GeneXpert Need to isolate the bug • Bugs: “need to bring them out, or go in and get them” • Often impractical or dangerous • Whole organ / body view of disease not available Inject radiotracer Uptake by target cells or bugs ENERGY Take pictures X-ray CT PET http://www.musc.edu/fnrd/primary.psych.images/page%2053.GIF Goo JM et al. Radiology 2000 • Rapid, and easily scalable to humans • Major investment by Oncologist to develop this technology for cancers • Now used extensively for monitoring cancer patients during clinical trials and also for patient care • Can these technologies be used in Infectious Diseases? • Provides spatial information, and holistic 3-D views of disease, not limited by sampling errors / contamination • Capable of visualizing processes deep within the body • Noninvasive (fundamental advantage): • study unaltered physiology • longitudinal assessments in the same individual • Relatively rapid • • • • Uniform cross-species platform for animal studies Easy translation to the clinic Allow adaptive designs for clinical trial Enabling personalized medicine Sensitivity Modality Agents H R Primary uses Examples Optical pM FMT fluorescent proteins X gene expression, tagging superficial structures GFP, RFP, NIRF probes BLI luciferin X gene expression, therapeutic monitoring fLuc rLuc X site-selectivity, protein labeling 99mTc-annex site-selectivity, gene expression, drug development 11C-RAC, 124I-FIAU, X CNS, prostate , heart , breast NAA, Cr, Cho, Glx, mI, 31P X cell trafficking, enzymatic activation poly-L-lysine, dendrimers, MION X drug-delivery, gene transfection human albumin (Optison) Nuclear SPECT 99mTc, 123/5I, X 111In nM PET 11C, 18F, 124I, X X 64/62/60Cu in V, 123I-A85380 64Cu-ATSM MRI µM spectroscopy endogenous metabolites contrast agents Gd, Mn, FeO X Ultrasound (10 µm) contrast agents perfluorinated microbubbles H=human, R=rodent Courtesy Marty Pomper (JHU) JOHNS HOPKINS U N I V E R S I T Y Center for Infection and Inflammation Imaging Research http://www.hopkinsmedicine.org/ci3r Working in a TB Lab! BSL-3 containment and anesthesia protocols • We use a commercially available portable anesthesia machine and isoflurane anesthesia • All animals are imaged only while inside of an appropriate BSL-3 container which is air tight, unbreakable and transparent • Temperature is monitored using an infrared thermometer and maintained using a heat lamp • More than 1000 M. tuberculosis-infected mice / rabbits have been anesthetized and imaged so far (some anesthetized for > 4 hrs) Lung CFU (log10) a AFB 8 c 4 0 0 14 28 42 Days after infection b Pan HB et al. Nature 2005. Davis SL et al. PLoS ONE 2009 Davis SL et al. Antimicrob Agents Chemother. 2009 Davis SL et al. Antimicrob Agents Chemother. 2009 Bug count (log scale) Old Method Bug counts 9 Untreated 6 1 – ineffective 3 – effective 3 Ineffective treatment 0 -2 0 2 4 8 12 Weeks after starting treatment Infection Effective treatment New method Functional Imaging PET Activity 1.8 Ineffective treatment 1.4 Effective treatment 1.0 0 4 8 • 2-weeks after infection, mice received 2 treatments (1 – ineffective, 2 – effective) • Mice killed at different times after starting treatment for counting bugs (old method) • Another group of mice imaged (new method) at the same times after starting treatment • Activity measured using imaging correlated with the effectiveness of the TB treatments (p < 0.033) • Imaging was real-time, compared with 4-weeks delay with the standard method • Relapse could be also be detected non-invasively 12 Weeks after starting treatment Davis SL et al. Antimicrob Agents Chemother. 2009 Serial PET activity in low-dose aerosol TB-infected lungs (segmented) of a C3HeB/FeJ mouse Partial segmentation of infected lungs. Holes appear in lieu of lesions. Complete segmentation of healthy lungs, used as template shape. Registration of the complete template shape onto the incomplete segmentation. Notice how the template fills in the holes of the lesions. After registration, a one-to-one correspondence between all CT and PET image sets is achieved making it possible to trace a region of interest (ROI) in one image and extract activities at corresponding locations across time-point Vidal C et al. Proceedings of the IEEE International Symposium on Biomedical Images 2009 Normalized mean PET Activity 4.5 Inf C3H 3.5 3.0 1.5 Inf Balb/c Uninf C3H 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 Harper et al. J Infect Dis. 2012 Time (minutes) Absorption Distribution Metabolism Elimination Biomarkers Toxicity Special Populations Courtesy Ed Weinstein (JHU) Lung Brain Liver Weinstein EA, Liu L et al. Antimicrob Agents Chemother. 2012 Pros Readily Available Readily Available Bacteria Specific Cons CT / MRI / US Not specific for bacteria or infection FDG-PET Not specific for bacteria or infection FIAU (Phase II) Difficult to synthesize Courtesy Ed Weinstein (JHU) • Readout • • • • better / worse (qualitative, quantative) infection or not? (Gen I) bacteria type? (Gen II) drug-susceptibility? (Gen III) INFECTION IDENTIFICATION EFFICACY • Purpose • diagnosis • monitoring disease • prognostic – correlates of protection, relapse • Setting • pre-clinical (uniform cross-species platform; allow unique insights into disease pathogenesis; expedite bench-to-bedside translation of new therapeutics) • clinical studies (multi-compartment PK; diagnostics; monitoring disease; disease pathogenesis; adaptive designs) • use in patients (diagnosis / monitoring; personalized medicine) • Due to the use of sub-pharmacological doses, the risk to human subjects is very limited in microdose studies. • Therefore, the requirements for preclinical safety testing are significantly simpler. • The FDA currently accepts the use of extended (14-days) single-dose toxicity studies in one mammalian species to support single-dose studies in humans. FDA. Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies. • Imaging of Infections Interest Group has been formed under the aegis of the World Molecular Imaging Society (WMIS). • The first meeting was held at the World Molecular Imaging Congress 2013 (Savannah, GA). • “The goal of this subgroup is to globally advance the implementation of imaging technologies as well as the development of new biomarkers for infections of various origin”, Neil Jarvis (Pretoria) , 2013 • We plan to centralize Infection Imaging initiatives under one roof and get endorsements from imaging and national infectious diseases societies - SNM, IDSA, PIDS, etc. • It is a good time to participate! Some “developing worlds” are more developed than you think accounts for a majority of TB worldwide World-at-Night Satellite Image Reveals Economic Activity Satellite Image of Earth at Night by Craig Mayhew and Robert Simmon, NASA GSFC http://geology.com/press-release/world-at-night/ Slums and skyscrapers Some “developing worlds”co-exist are more developed than you think PET scans for just Rs 7,500 Kounteya Sinha, TNN 2005, 11.43pm of India accounts for Jula 23, majority ofIST, TBTimes worldwide World-at-Night Satellite Image Reveals Economic Activity Satellite Image of Earth at Night by Craig Mayhew and Robert Simmon, NASA GSFC http://geology.com/press-release/world-at-night/ • Multidisciplinary approach (biologists, chemists, mathematicians, clinicians) for developing imaging tracers for infection & inflammation • Goals • develop “pathogen-specific” imaging tracers • monitor the pathogen and their host-microenvironment simultaneously • track “hideouts” of infections in the body • better understanding of disease pathogenesis • Innovative • uniform cross-species platform for animal studies • allow unique insights into disease pathogenesis • expedite bench-to-bedside translation of new therapeutics • Translational • diagnosis / monitoring disease • understand pathogenesis • multi-compartment PK - phase 0 studies • personalized medicine Potential to change how the world sees infections National Institutes of Health (OD, NHLBI, NIAID) Thanks Organization Mariah Klunk Jin Lee Pauline Myles Alvaro Ordonez NIAID (DAIDS, CIDI, DMID) Richard Hafner Dima Hammoud Peter Kim Karen Lacourciere Dan Mollura Abstract Reviewers Kevin Francis (PerkinElmer) Dima Hammoud (NIH) Sanjay Jain (JHU) Philana Lin (Univ. of Pitts) Speakers Sanjay Jain (JHU) Clif Barry (NIH) Dima Hammoud (NIH) Marie-France Penet (JHU) Assaf Gilad (JHU) Catherine Foss (JHU) Ed Weinstein (JHU) Kevin Francis (PerkinElmer) Lloyd Miller (JHU) Peter Tonge (Stony Brook Univ.) Ulas Bagci (NIH) Bruno Jedynak (JHU) Welcome Prof. Chris Meier Vice-Dean for Research Faculty of Sciences University of Hamburg