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| 19.1 Gene Therapy Successes and SetbacksAdenosine Deaminase Deficiency-Early Success 1. In 1986 PEG-ADA was first used to treat ADA-deficient SCID. Initial results were promising. 2. In 1990, a four-year old girl with ADA-deficient SCID, became the first person treated with gene therapy. 3. The gene therapy used in 1990 involved infusions of T-cells that had been transduced with a gene for ADA. This therapy resulted in partial restoration of immune function in the patient. Ornithine Transcarbamylase Deficiency-A Setback 1. In 1999, gene therapy for OTC deficiency led to a tragic death of an eighteen-year old patient. 2. The patient died as the result of an unexpected severe immune reaction to the virus used to deliver the OTC gene. All gene therapy protocols were carefully reviewed. A Success in the Making-Canavan Disease 1. Canavan disease results in demyelination of brain neurons. 2. Restoration of aspartoacylase activity via gene therapy seemed to stop demyelination in a human patient. 19.2 The Mechanics of Gene Therapy 1. Gene therapies replace malfunctioning or absent genes. 2. Ex vivo gene therapy involves injection of engineered cells into patients. 3. In vivo gene therapy involves injecting the vector directly into the body. Treating the Phenotype 1. Protein-based therapies replace gene products and treat the phenotype. Germline Versus Somatic Gene Therapy 1. Germline gene therapy targets gametes or fertilized ova and is heritable. 2. Somatic gene therapy targets various types of somatic tissue as well as cancer cells and is not heritable. Sites of Somatic Gene Therapy 1. Stem cells from bone marrow and other tissues are being pursued as sites for gene therapy since under certain conditions they can specialize into cell types present in a variety of different tissues. 2. Genetically altered endothelium implanted in blood vessels secretes needed proteins into the bloodstream. 3. Skin cells can be genetically altered in culture, expanded, then grafted onto animals, where they secrete foreign gene products. 4. Muscle is potentially a good target for gene therapy because it is accessible, near a blood supply, and abundant. 5. The liver is the largest organ, has many functions and can regenerate. Liver cells from an individual can be removed, genetically altered, and grafted back to the host. Alternatively, genes can also be introduced into liver cells by infection with engineered viruses introduced into an artery leading to the liver. 6. Lung disorders can be targeted using disabled cold viruses in aerosols or liposomes that can deliver genes to lung cells. 7. Nerve cells can be exposed to altered herpes viruses, or treated by genetically engineering fibroblasts or glia around them. 8. Cancer cells are targets for two different approaches of gene therapy. Suicide gene therapy delivers genes that cause cancer cells to self-destruct. Cancer vaccines mark tumor cells for destruction by the immune system. Gene Delivery 1. Vectors for delivering genes include liposomes and viruses. 2. Viral vectors differ in the type of cell they can enter, and in how large a gene they can carry. 3. Ex vivo gene therapy removes cells from a patient, manipulates them, and returns them. 4. In situ gene therapy delivers a gene directly to an accessible body part. 5. In vivo gene therapy delivers the vector into the body. 6. Chimeraplasty is a form of gene surgery that uses small RNA-DNA oligonucleotides to stimulate DNA repair and restore a normal gene sequence. 19.3 A Closer Look: Treating Sickle Cell Disease 1. Sickle cell hemoglobin aggregates and deforms the red cells. This results in numerous phenotypic effects. 2. Blood transfusions and bone marrow transplants have been used to treat sickle cell disease. In a few cases, bone marrow transplants have led to complete cures. 3. In some cases a drug, hydroxyurea, is used to reactivate alternative genes (i.e. fetal hemoglobin) to treat sickle cell disease. 19.4 Genetic Screening and Genetic CounselingGenetic Counselors Provide Diverse Services 1. A genetic counselor provides information to individuals, couples, and families on modes of inheritance, recurrence risks, genetic tests, and treatments. 2. A "nondirective" approach is used by genetic counselors. 3. The counselor provides information to promote informed decision making but does not offer an opinion or suggest a course of action and must be respectfully sensitive to individual choices. Scene from a Sickle Cell Disease Clinic 1. Newborn children with sickle cell disease can be identified by screening tests. 2. Genetic counselors meet with the family a few days after the child's birth and provide vital information about treatment, support groups, and recurrence risk. Genetic Counseling Quandaries and Challenges 1. Genetic information can present difficult situations for counselors and patients due to confidentiality and health issues. Perspective: A Slow Start, But Great Promise 1. Gene therapy is working but future breakthroughs will require advances in vectors that will allow targeted gene transfer that provides sustained and safe genetic correction without alerting the immune system. |