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Genomics and Therapies: Progress and Prospects

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Genomics and Therapies: Progress and Prospects Genomics and therapies: Progress and prospects Dr Rana Bazzi PhD in Genetics University of Nottingham, UK • Molecular Medicine Gene-based therapies • Regenerative Medicine Stem cells therapies The progress in medicine is due to advances in molecular biology • Synthetic oligonucleotides (1979) • Vectors of eukaryote expression (1982) • Transgenesis by micro injection in murin ovocytes ( 1982) • PCR (1989) • Gene targeting by homologous recombination in embryonic stem cells (ES) (1987) • Gene cloning in yeast chromosomes in YAC(1987) and BAC (1992) • Chips and microarrays (1995) • Post-transcriptional inactivation by iRNA (2006) • Nanotechology and nanochips • Bioinformatics Transgenesis- the knockout mice • mdx mouse: 1st animal model for dystrophinopathies (Duchenne and Becker) • Other knockout mice: - Obesity - heart disease - diabetes, arthritis - substance abuse - Anxiety - aging - Parkinson disease Transgenic mice Obese mouse oncomice Transgenesis: Humanized mouse • Obtained with classical transgenesis or homologous recombination • powerful research tool to decipher in vivo human physiology and to test drug efficacy • Caveats: false positives and false negatives. Transgenesis Methods The Pronucleus Method NATURE PROTOCOLS | VOL.2 NO.5 | 2007 Mutant mice generated from embryonic stem-cell lines should further understanding of human disease. WELLCOME LIBRARY, LONDON Mutant mice generated from embryonic stem-cell lines should further understanding of human disease. WELLCOME LIBRARY, LONDON Gene-based therapy • Prerequisite: - Gene knowledge - Physiopathological mechanisms • 5 therapeutic strategies Genomics Epigenomics transcriptomics Proteomics Cellular Gene-based therapy: Genomics Genome manipulation : Target the mutant gene and correcting the mutation (approaches of classic gene therapy) Target a paralogous gene and reactivate it Target one or more genes implicated in a physiopathological cascade Classic gene therapy-outline • Somatic versus germ-line gene therapies • Strategies for gene therapy - In vivo, ex vivo • Types of gene therapy: - Gene augmentation, gene inhibition , killing cells. • Gene therapy vectors: - Viral and non viral vectors: advantages and disadvantages • Future of gene therapy In vivo and ex vivo gene therapy Gene therapy • Can be defined as the treatment of human disease by the transfer of foreign DNA via a vector into a patient’s cells • Alternative therapy • It is an application for recombinant DNA technology • Ex: cystic fibrosis, Alzheimer, Duchenne muscular dystrophy, haemophilia, and potentially diabetes mellitus and cardiovascular disease. • Gene therapy research is under the supervision of regulatory bodies Early trials were deceiving …..why? In 1999, 18-year-old Jesse Gelsinger died 4 days after starting the treatment. In 2000, a team led by Alain Fischer at Necker Hospital, Paris, replaced faulty gene causing X-SCID disease but patients developed leukemia. Somatic versus germ-line gene therapy • Somatic gene therapy: - DNA transfer to some cells other than germ-line cells, thus - Results are restricted to the treated patient • Germ-line gene therapy: - DNA transfer to egg or sperm, thus - Results are passed on to future generations - Technical risks to introduce defects into the embryo - Unethical to apply Current gene therapy is exclusively somatic gene therapy Principles of gene transfer • Classical gene therapies normally require: - An expression cassette of the cloned gene cDNA ensuring high level expression. - Delivery system - Efficient transfer - Following gene transfer, the inserted genes may integratd into the genome of the cell or remain episomes. Gene transfer • Two terms are used depending on the vector used: 1)Transduction: virus mediated gene transfer. Here the virus is genetically altered (remove disease- causing genes and insert therapeutic genes). 2)Transfection: non-viral mediated gene transfer. This can be done by: - Direct injection - Liposomes - Receptor-mediated endocytosis Gene transfer vectors: Advantages and disadvantages (1) Method of gene transfer Advantages Disadvantages Retrovirus - High expression of DNA - Risk for insertional -Long term expression mutagenesis -Non toxic -Requires dividing cells - Limited size of DNA insert (<8kb) Adeno-associated virus -No adverse effects Limited size of DNA insert (AAD) -Can infect dividing and (<5kb) non-dividing cells Adenovirus -Can infect dividing and - Very immunogenic non-dividing cells - Transient expression of -Large DNA insert (≤35kb) exogenous DNA -No risk for insertional mutagenesis Gene transfer vectors: Advantages and disadvantages (2) Method of gene Advantages Disadvantages transfer Direct injection Straightforward - Inefficient DNA transfer -Used only for certain tissues -Requires large amount of DNA Liposomes Large amount of DNA - Inefficient DNA transfer - Poor expression of exogenous DNA Receptor-mediated Efficient transfer of DNA Poor expression of endocytosis exogenous DNA Adenovirus vectors In vivo liposome gene delivery There are several types of gene therapy 1- Gene addition therapy - The mutant gene is with a loss-of-function effect - The approach consists of inserting a normal copy of the gene. - Ex: PKU 2- Gene correction therapy - The mutant gene is with a gain-of-function effect - The approach consists of inhibiting the expression/replacing of the mutant gene by homologous recombination - Ex: infectious diseases, cancers Clinical Trials in Gene Therapy 1. Ornithine Transcarbamylase Deficiency (OTC) • In vivo adenoviral delivery of CFTR to the liver 2. Hemophilia • In vivo (either IM or intra-hepatic artery) of recombinant adeno-associated virus for factor VIII (F8) gene . 3. Severe Combined Immunodeficiency • Retroviral infection of human hematopoeitic stem cells ex vivo, etc… Hemophilia Gene Therapy • Early successes of therapeutic expression in mice and dogs • Recent (2010) successes of therapeutic expression in humans (Nathwani, A et al., abstract, Annual Meeting, American Society of Hematology, 2010) • Adults with hemophilia B were injected intravenously the AAV8 vector containing the human FIX gene • The cost of vector preparation and testing was about $30,000 per patient Factors that reduce the effectiveness of gene therapy • Failure to achieve stable expression therefore Patients will have to undergo multiple rounds of gene therapy. • Immune response • Viral vectors are biological threats • Multigene disorders The Nobel Prize in Physiology or Medicine 2009 for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase". Elizabeth H. Blackburn Carol W. Greider Jack W. Szostak Future of gene therapy… • Advances in vector technology that reduce toxicity and increase efficiency • Demonstrate continued efficacy • To achieve transfer to patients with neutralizing antibodies • To ensure that gene therapy approach is safe in the long term • Nanotechnology in gene therapy Gene-based therapy: Genomics Genome manipulation : Target the mutant gene and correcting the mutation (approaches of classic gene therapy) Target a paralogous gene and reactivate it Target one or more genes implicated in a physiopathological cascade Strategy of reactivating a paralogous gene • Potential strategy • The mutant gene has a paralogous gene that is active at some developmental stage • How is it possible to reactivate a sleeping gene? - Epigenetic reprogrammation - Trans activation of the promoter • Applications: - Globin gene (sickle cell anemia, beta- thalassemia) α2β2 or α2γ2 - Dystrophin gene (DMD) Schematic representation of the globin gene loci Case study: the DMD • Duchenne muscular dystrophy (DMD) • The most prevalent lethal genetic disorder in children • Caused by mutations in the 2.2-MB dystrophin gene, • Absence of dystrophin and the dystrophin– glycoprotein complex (DGC) from the sarcolemma leads to severe muscle wasting and eventual respiratory and/or cardiac failure • There is presently no effective therapy for DMD • Methods to increase expression of UTR, utrophin gene, a dystrophin paralog, show promise as a treatment for DMD. Gene-based therapy: Genomics Genome manipulation : Target the mutant gene and correcting the mutation (approaches of classic gene therapy) Target a paralogous gene and reactivate it Target one or more genes implicated in a physiopathological cascade Strategies of targeting a physiopathological cascade . Overexpress or inhibit one or many genes implicated in a pathological process by: For one gene: DNA transfer Search for these genes by genomic screening (pharmacogenomics) Applications: cancers . Killing cells - The aim is to kill cells - The approach consists of introducing a suicide gene (gene transfer) which product is toxic - Ensures appropriate cell targeting - Ex: cancers Gene-based therapy: epigenomics • Aims to modify chromatin structure in order to render it transcriptionnally active/inactive. • The pathologies to be targeted are of epigenetic origin • If the pathology involves a defective closed chromatin, then the strategy consists of using chemicals that can inhibit: • DNA-methylase or • Histone deacetylase Applications: Oncology Limitations • Non selective targeting pleiotropic side effect • Advantages: - Diffusable molecules - Reversable effect Gene-based therapy: transcriptomics • Target RNA • These strategies rely on the modification of the mutated gene's expression in vivo by modulating pre- mRNA splicing, mRNA stability or mRNA translation • Small RNA revolution: microRNA (miRNA), small interfering RNA (siRNA), etc… The Nobel
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