Lecture Medical biotechnology

Medical biotechnology including diverse discipline dedicated to improving human health Drug production (use for treatment of infectious, cardiovascular diseases…) Diagnostics (determine or identify a possible disease or disorder) Gene therapy (use of DNA as a pharmaceutical agent to treat disease) Pharmacogenomics (influence of genetic variation on drug response in patients by correlating gene expression or SNP with a drug's efficacy or toxicity) Diagnostics and gene therapy It mostly focuses on: Disease prevention Disease diagnosis, Disease treatment A disease is a condition that impairs normal bodily functioning Examples of diseases include: heart disease, cancer, diabetes, HIV/AIDS, inherited diseases,… Pharmaceutical industry The Food and Drug Administration (FDA) is a US regulatory agency that oversees food, drugs and devices It also monitors clinical trials and approves new drugs that have succeeded Pharmaceutical companies are those licensed to discover, develop, market, and distribute drugs Drugs (according to the FDA) are defined as substances intended for use in diagnosis, cure, treatment, or prevention of disease Drug Production Screening: is a laborious and costly process—only in every 5,000 to 10,000 compounds screened eventually becomes an approved drug To screen an antibiotic, it is first placed in a bacterial culture If the antibiotic is effective, it is next tested on infected laboratory animals to study the safety and efficacy of the new drug Selecting: A new drug is selected for testing on humans only if it either promises to have therapeutic advantages over drugs already in use or is safer Clinical investigations, or "trials," of the drug on human patients First: a small group of healthy volunteers to determine and adjust dosage levels, and monitor for side effects Second: a larger group of volunteers or carefully selected patients Third round: a very large panel, sometimes upwards of 10,000 individuals Approval of The U.S Food and Drug Administration's (FDA), and Center for Drug Evaluation and Research (CDER) for commercial use The entire process, from the first discovery of a new compound to FDA approval, can take over a decade and cost hundreds of millions of dollars Preclinical Testing The first step is to identify a potential drug candidate, called a lead compound Once a lead compound has been identified in the lab, it begins years of testing to evaluate its safety and efficacy In vitro studies are carried out to identify the way it interacts with its target After that, tests on model organisms (animals that have the targeted disease) take place This usually lasts around 6-7 years Preclinical Testing Many preclinical tests include pharmacokinetics - the study of how drugs move through living organisms Four processes are examined in pharmacokinetic studies: absorption, distribution, metabolism & excretion Investigational New Drug (IND) Application After preclinical testing is completed, a company files an IND application with the Food & Drug Administration (FDA) prior to any testing on humans This application includes: • Results of preclinical studies • Chemical structure & properties • Pharmacokinetics • Side effects • Clinical trial plan Clinical Trials Clinical trials are a process of testing products prior to approval of a drug or treatment plan for widespread use in humans • Begin after the use of model organisms • Most are classified into phases: I, II, & III • All participants go through informed consent process (given facts about risks & benefits) Phase I • Initial studies of drug in a small number (20 -80) of healthy volunteers to determine its safety • Intended to determine safe dose range • Exceptions are made for highly toxic treatments (ex cancer or HIV) - in this case appropriate patients selected •Pharmacokinetic studies determine dosing & limitations of use Take months - year to complete Phase II • Larger groups of people with the disease (100 - 300) are used to study efficacy • Safety is further evaluated • Side effects also studied • Optimal dose strength and schedule (once or twice daily) • Dose-response relationship evaluated to visualize drug performance Usually about years to complete Transcription map of human adenovirus serotype Major Late Promoter Ψ required for the encapsidation of the Ad genome ITRs are required for viral DNA replication CME.the oncologist.com Different generations of adenoviral vectors GeneTherapy (2005)12, S18–S27 Advantages of using a recombinant Adenovirus Helper independent Ad can accommodate up to 7.5 kb of foreign DNA (deletion of E1 and E3 regions) Ad can encapsidate a viral DNA molecule slightly bigger than the normal DNA (105%) To the E1 and E3 of Ad have been deleted Helper-dependent Ad can accommodate up to 36 kb of foreign DNA (The entire adenoviral genome, with exception of the 5’ and 3’ ITRs and packaging signal is removed) • • rAd are considered the safest adenoviral vectors due to their lack of viral proteins rAd can only be propagated in the presence of a helper adenovirus Advantages of using a recombinant Adenovirus No insertional mutagenesis; remains epichromosomal Retroviruses integrate randomly into the host chromosome and can inactivate genes or activate oncogenes Ad remains epichromosomal and therefore does not interfere with other host genes AdenoVator™ Principle The AdEasy system for Ad vector production Generation of gutless adenovirus using the Cre/loxP system GeneTherapy (2005)12,S18–S27 The Cre/loxP system for generating HDAds (helper-dependent adenovirus) Viruses, 2010, 2, 1886-1917 Site-directed integration of foreign DNA Site-specific recombination mechanisms Site-specific integration An episomally replicating plasmid (pEPI) ... production systems different production systems http://www.microbialcellfactories.com/content/8/1/17 Medical biotechnology including diverse discipline dedicated to improving human health Gene therapy