Chapter 065. Gene Therapy in Clinical Medicine (Part 1)

Harrisons Internal Medicine Chapter 65. Gene Therapy in Clinical MedicineGene Therapy in Clinical Medicine: IntroductionGene transfer is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or small molecule. Because delivery of naked DNA or RNA to a cell is an inefficient process, most gene transfer is carried out using a vector, or gene delivery vehicle. These vehicles have generally been engineered from viruses by deleting some or all of the viral genome and replacing it with the therapeutic gene of interest under the control of a suitable...
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Chapter 065. Gene Therapy in Clinical Medicine (Part 1) Chapter 065. Gene Therapy in Clinical Medicine (Part 1) Harrisons Internal Medicine > Chapter 65. Gene Therapy in ClinicalMedicine Gene Therapy in Clinical Medicine: Introduction Gene transfer is a novel area of therapeutics in which the active agent is anucleic acid sequence rather than a protein or small molecule. Because delivery ofnaked DNA or RNA to a cell is an inefficient process, most gene transfer is carriedout using a vector, or gene delivery vehicle. These vehicles have generally beenengineered from viruses by deleting some or all of the viral genome and replacingit with the therapeutic gene of interest under the control of a suitable promoter(Table 65-1). Gene transfer strategies can be described in terms of three essentialelements: (1) a vector, (2) a gene to be delivered, and (3) a relevant target cell towhich the DNA or RNA is delivered. The series of steps in which the donatedDNA enters the target cell and begins expression is referred to as transduction.Gene delivery can take place in vivo, in which the vector is directly injected intothe patient or, in the case of hematopoietic and some other target cells, ex vivo,with removal of the target cells from the patient, followed by return of themodified autologous cells after gene transfer in the laboratory. The latter approachoffers opportunities to integrate gene transfer techniques with cellular therapies(Chap. 67). Table 65-1 Characteristics of Gene Delivery Vehicles Viral Vectors Features Retroviral Lentiviral Adenoviral AAV Hum Foamy Vir Viral RNA RNA DNA DNA RNAgenome Cell Yes G1 phase No No Nodivision Viral Vectors Features Retroviral Lentiviral Adenoviral AAV Hum Foamy Virrequirement Packaging 8 kb 8 kb 8–30 kb 5 kb 8.5 klimitation Immune Few Few Extensive Few Fewresponses tovector Genome Yes Yes Poor Poor Yesintegration Long- Yes Yes No Yes Yesterm expression Main Persistent Persistent Highly Elicits Persi Viral Vectors Features Retroviral Lentiviral Adenoviral AAV Hum Foamy Viradvantages gene transfer in gene transfer in effective in few gene expre dividing cells transduced transducing inflammatory in both div tissues various tissues responses, and nondiv nonpathogenic cells Main Theoretical Might Viral Limited Indisadvantages risk of insertional induce capsid elicits packaging of a s mutagenesis oncogenesis in strong immune capacity packaging (occurred in 3 some cases responses system cases) Note: AAV, adeno-associated virus; HSV, herpes simplex virus; SV,sarcoma virus Gene transfer technology is still under development and protocols areexperimental. Gene therapy is one of the most complex therapeutic modalities yetattempted, and each new disease represents a therapeutic problem for whichdosing, safety, and efficacy must be defined. Nonetheless, gene transfer remainsone of the most powerful concepts in modern molecular medicine and has thepotential to address a host of diseases for which there are currently no cures or, insome cases, no available treatment. Over 5000 subjects have been enrolled in genetransfer studies, and serious adverse events have been rare. Gene therapies arebeing developed for a wide variety of disease entities (Fig. 65-1).