Molecular Imaging and Genomics Radiology Dept, Ruijin Hospital SSMU
Molecular Imaging and Genomics Radiology Dept. , Ruijin Hospital SSMU
Technology development to spearhead the revolution in medicine Radiology Imageology Molecular Imaging Genomics and Molecular ima
G e n o m i c s a n d M o l e c u l a r I m a g i n g Molecular Imaging Imageology Radiology Technology development to spearhead the revolution in medicine…
Molecular Imaging Components tic Pha PET MRL MRSI Biochemistry Novel agents/tracers DNA/Protein MicroArrays Diagnosti Tuvajev, Blasberg Larson MSKcC Biotech Imaging Physics, MOLECULAR Molecular Engineering IMAGING Core Technologies Integrated Diagnostics 2. Image Analysis ivo Imaging tie rugs needing more specific disease diagnosis to Applied Genomics genetic data on patient Chemistry libraries Pharmacology armaceuticals Integrating Critical Skills. Imaging with Diagnostics. Diagnostics with Therapeutics
G e n o m i c s a n d M o l e c u l a r I m a g i n g DNA/Protein MicroArrays Affymetrix Integrated Diagnostics: in Vivo Imaging tied to Applied Genomics Molecular Imaging Components Source: Uzgiris, GE CRD Tjuvajev, Blasberg, Larson, MSKCC Drugs needing more specific disease diagnosis or genetic data on patient Chemistry libraries Novel agents/tracers Biochemistry Pharmacology MOLECULAR IMAGING Molecular Biology PET, MRI, MRSI Core Technologies: 1. Hi Sens/Spec Imaging 2. Image Analysis Imaging Physics, Engineering Integrating Critical Skills… Imaging with Diagnostics … Diagnostics with Therapeutics
Broad Based Technology Platform Approach Fundamental Technology Hurdles Platform Concepts Project Disease Targets Definition Industry and Academic Partnerships Technology Focus Areas: MR and pet diagnostic agent Biomarker Discovery and Clinical IVD Biomedical Informatics and Computing Clinical Translation and Imaging Optimization Optical Imaging Genomics and Molecular i magi n
G e n o m i c s a n d M o l e c u l a r I m a g i n g • Fundamental Technology Hurdles • Platform Concepts • Disease Targets • Industry and Academic Partnerships Project Definition Technology Focus Areas: • MR and PET Diagnostic Agents • Biomarker Discovery and Clinical IVD • Biomedical Informatics and Computing • Clinical Translation and Imaging Optimization • Optical Imaging Broad Based Technology Platform Approach
Molecular tools Disease Specific Metrics Anatomical Compartments (Blood, Lipophilic Tissue(fat) letabolic Active(muscle), Elimination(liver, kidney)…) Physio-chemical (Metabolism, Oxygenation, Diffusion, pH, Transport Characteristics, Elimination Phagocytosis, Cell-type Specific.) Biological (Cell Surface Receptors, Antigens, Transporters, Gene Sequences, Proteins, Enzymatic Activity Post Translational Modification.) Vulnerable Plaque Imaging Molecula Molecular Imaging: Pathology Specific Molecular Markers
G e n o m i c s a n d M o l e c u l a r I m a g i n g Molecular Tools Compartments (Blood, Lipophilic Tissue (fat), Metabolic Active (muscle), Elimination (liver, kidney)…) Physio-chemical (Metabolism, Oxygenation, Diffusion, pH, Transport Characteristics, Elimination, Phagocytosis, Cell-type Specific…) Biological (Cell Surface Receptors, Antigens, Transporters, Gene Sequences, Proteins, Enzymatic Activity, Post Translational Modification…) Anatomical Molecular Molecular Imaging: Pathology Specific Molecular Markers Disease Specific Metrics Vulnerable Plaque Imaging
CV: Myocardial Infarction Societal cost 6M emergency room visits/year(US); 2.5M admitted to critical care unit 34K sent home improperly Genomic Lipoprotein a(positive Scan/PHarma Therapy prognosIs · Targeted SPECT agent · Thrombolytic to ⅣvD (apoptosis and cellular restore blood flow (negative prognosis · Platelet activation and viability measure to affected tissue fibrinogen metrics ·Eva| uation of viab|ev Anti-apoptotic Suggest plaque rupture, necrotic v pre-apoptoti agent(caspase-3 fissure and thrombosis heart tissue and inhibitor )to allow hemorrhage potential pre-apoptotic recovery Symptomology Angina(chest pain) Standard blood gas erapy Evaluation electrolyte and blood chemistry measures Genomics and Molecular i magi n
G e n o m i c s a n d M o l e c u l a r I m a g i n g CV: Myocardial Infarction Societal Cost 6M emergency room visits/year (US); 2.5M admitted to critical care unit 34K sent home improperly Genomic • Lipoprotein A (positive prognosis) • C-reactive protein (negative prognosis) Symptomology • Angina (chest pain) • Standard blood gas, electrolyte and blood chemistry measures IVD • Platelet activation and fibrinogen metrics • Suggest plaque rupture, fissure and thrombosis Scan/DPharma • Targeted SPECT agent (apoptosis) and cellular viability measure • Evaluation of viable v necrotic v pre-apoptotic heart tissue and hemorrhage potential Therapy • Thrombolytic to restore blood flow to affected tissue • Anti-apoptotic agent (caspase-3 inhibitor) to allow pre-apoptotic recovery Therapy Evaluation N N NH O O
Comprehensive Molecular Diagnostics Approach Program in Cardiovascular Disease Basis of research focus and target selection Disease focus Largest unmet clinical need . Atherosclerosis Diagnostic affects therapy choice Plaque burden outcome Inflammatory component, thrombotic risl Surrogate for disease modifying claims Endothelial dysfunction Diagnostic-therapeutic co-development .Ischemic heart disease Development of molecular imaging agent(s) Transient ischemia Development of clinicalIVD test Ischemic footprint and progression Platform Technologies Targets molecular Imaging Agent Molecular Imaging Agents Reptating polypeptide ( Mri Oxidized lipoproteins and their receptors Targets in inflammatory cascade Iron oxide nanoparticles(MRi) F-18 labeled peptides(PEt) ° Apoptosis Engineered antibody targeting(PET) In Vitro Diagnostics pathway informatics tool Ischemia modified proteins Normal Thrombosis ATHIT Stress test Genomics and Molecular ima
G e n o m i c s a n d M o l e c u l a r I m a g i n g Approach • Basis of research focus and target selection • Largest unmet clinical need • Diagnostic affects therapy choice & outcome • Surrogate for disease modifying claims • Diagnostic-therapeutic co-development • Development of molecular imaging agent(s) • Development of clinical IVD test Comprehensive Molecular Diagnostics Program in Cardiovascular Disease Disease Focus •Atherosclerosis • Plaque burden • Inflammatory component, thrombotic risk • Endothelial dysfunction •Ischemic heart disease • Transient ischemia • Ischemic footprint and progression Targets •Molecular Imaging Agents •Oxidized lipoproteins and their receptors •Targets in inflammatory cascade •Apoptosis •In Vitro Diagnostics •Ischemia modified proteins Platform Technologies •Molecular Imaging Agent •Reptating polypeptide (MRI) •Iron oxide nanoparticles (MRI) •F-18 labeled peptides (PET) •Engineered antibody targeting (PET) •Pathway informatics tool Normal Fatty Streak Vulnerable Plaque Occlusive AS Plaque Rupture/ Thrombosis Clinically Silent Stress test
CNS Disease: Comprehensive Imaging Program Approach and opportunity Opportunity: disease modify ing therapy Expanding to Diagnostic Agents pipeline Early differential diagnosis Disease Focus Diagnosis to affect therapy choice ·A| zheimer’ s disease and other dementia outcome AB processing, aggregation, and Surrogate for disease modifying claims clearance Diagnostic-therapeutic co-development Brain iron metabolism and overload Application of high field (3T)MRI Inflammation and the role of microglia Development of molecular imaging agent(s) Multiple Sclerosis Disease pathogenesis molecular Autoimmune response and inflammation mechanisms Platform Technologies argets 3T MR Imaging Molecular Imaging Agents-03 Structural mri Ab and nft burden · Brain iron imaging Targets in inflammatory cascade Proton Spectroscopy Apoptosis .Platform Technologies Molecular mechanisms Brain tissue analysis, histolog Role of metals in neurotoxicity Model of brain iron metabolism · Quantitative MR Computer-aided prognostics
G e n o m i c s a n d M o l e c u l a r I m a g i n g Approach and opportunity • Opportunity: disease modifying therapy pipeline • Early differential diagnosis • Diagnosis to affect therapy choice & outcome • Surrogate for disease modifying claims • Diagnostic-therapeutic co-development • Application of high field (3T) MRI • Development of molecular imaging agent(s) • Disease pathogenesis & molecular mechanisms CNS Disease: Comprehensive Imaging Program Expanding to Diagnostic Agents Disease Focus • Alzheimer’s disease and other dementia • Ab processing, aggregation, and clearance • Brain iron metabolism and overload • Inflammation and the role of microglia • Multiple Sclerosis • Autoimmune response and inflammation Targets •Molecular Imaging Agents – ‘03 • Ab and NFT burden • Targets in inflammatory cascade • Apoptosis •Molecular Mechanisms • Role of metals in neurotoxicity • Model of brain iron metabolism Platform Technologies •3T MR Imaging • Structural MRI • Brain iron imaging • Proton Spectroscopy •Platform Technologies • Brain tissue analysis, histology, ex vivo imaging • Quantitative MRI •Computer-aided prognostics
A Nove/ MR Agent for Tumor Angiogenesis Evaluation Long and Narrow Linear Molecules Could Penetrate Tumor Endothelium Conceptual Illustration coiled molecule interstitium Paramagnetic ion,G● linear molecule lumen small molecule Chelator DTPA o matrix endothelium Backbone polymer, polylysine peptide Agent Endothelium Penetration Agent Synthesis Genomics and Molecular ima
G e n o m i c s a n d M o l e c u l a r I m a g i n g Long and Narrow Linear Molecules Could Penetrate Tumor Endothelium interstitium matrix endothelium lumen Agent Endothelium Penetration coiled molecule small molecule linear molecule Paramagnetic ion, Gd Chelator, DTPA Backbone polymer, polylysine peptide Agent Synthesis Conceptual Illustration A Novel MR Agent for Tumor Angiogenesis Evaluation
A Novel MR Agent for Tumor Angiogenesis Evaluation Tumor Contrast Depends on the conformation of the agent Rat #1 with Tumor Rat #2 with Tumor Linear polymer, 0.025 mmol Gd/kg Linear Polymer, 0.025 mmol Gd/kg Contrast Agents 2. Semi-extendad 3. semi-coiled 6. Gd-DTPA Coiled Polymer, 0.025 mmol Gd/kg Contrast Agent Type Rat Mammary Adenocarcinoma in Female Fisher Rats 24 hours After Agent Injection Genomics and Molecular ima
G e n o m i c s a n d M o l e c u l a r I m a g i n g Rat Mammary Adenocarcinoma in Female Fisher Rats 24 hours After Agent Injection Rat #1 with Tumor Linear polymer, 0.025 mmol Gd/kg Rat #2 with Tumor Linear Polymer, 0.025 mmol Gd/kg Control Coiled Polymer, 0.025 mmol Gd/kg Tumor Contrast Depends on the Conformation of the Agent A Novel MR Agent for Tumor Angiogenesis Evaluation