Objectives: Gene Therapy See lecture objectives on web Read pages 311-327 (chapter 13) in text Early Human Gene Therapy Experiments ADA Deficiency Gene Therapy in the News Heard at the Genetics Clinic:

Objectives: Gene Therapy See lecture objectives on web Read pages 311-327 (chapter 13) in text Early Human Gene Therapy Experiments ADA Deficiency Gene Therapy in the News Heard at the Genetics Clinic: www.phwiki.com

Objectives: Gene Therapy See lecture objectives on web Read pages 311-327 (chapter 13) in text Early Human Gene Therapy Experiments ADA Deficiency Gene Therapy in the News Heard at the Genetics Clinic:

Parisi, Jim, Host has reference to this Academic Journal, PHwiki organized this Journal “Technology always goes as long as ward. There are radical new technologies that surprise us all the time. And we’ve got a long time in the future to go. This is my conclusion: Human evolution will be self-driven.” Lee Silver, PhD, 3/98 Objectives: Gene Therapy See lecture objectives on web Read pages 311-327 (chapter 13) in text Germline vs. somatic gene therapy Gene therapy vectors (advantages in addition to disadvantages): Retrovirus Adenovirus Adeno-associated virus (AAV) Non-viral vectors in vivo vs ex vivo gene therapy Current status of human gene therapy experimentation Stem cell therapy Pharmaceuticals produced by recombinant DNA technology

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Early Human Gene Therapy Experiments Marty Cline human experiments- 1980 NeoR/TIL marking studies- 1989 ADA/peripheral blood T cells- 1990 LDL receptor/ex vivo hepatocytes- 1992 HLA-B7 Melanoma- 1992 ADA/bone marrow, cystic fibrosis, multiple cancer protocols, HIV ADA Deficiency Rare Immunodeficiency (fatal in childhood) Advantages as model as long as gene therapy: Regulated expression not necessary Low level expression sufficient Site of synthesis not critical Potential as long as in vivo selection Bone marrow suitable target Problems: Difficulty achieving high level, stable expression Other effective therapy: PEG-ADA therapy, allogeneic/haploidentical BMT First human experiments per as long as med 1991 (2 patients) successful; simultaneous PEG-ADA therapy

Gene Therapy in the News October 1999- 1st reported death due to gene therapy November 1999- Failure of scientists to report gene therapy trial deaths to FDA/RAC April 2000- 1st definite success of human gene therapy (SCID-X1) Cavazzana-Calvo, et al. Science 288:669. Factor IX gene therapy (hemophilia B) promising In vivo AAV: Kay et al. Nat.Gen. 24:257, 2000. Ex vivo fibroblast: Roth et al. NEJM 344:1735, 2001. Heard at the Genetics Clinic: “Can you take out the bad gene” “Can you fix that gene” “Can you remove the extra chromosome” “By the time my daughter gets the disease, will be there be gene therapy to treat it, or at least to her babies” “Are doctors working on gene therapy as long as this” Concerns about Genetic Engineering The Council as long as Responsible Genetics “in utero gene therapy ef as long as ts will result in eugenic practices” Mothers as long as Natural Law “fundamental weaknesses of genetic concepts in addition to health hazards” Washington Biotechnology Action Council “Genetic engineering is a big business major decisions are made in the boardrooms of corporations in addition to by a h in addition to ful of scientists in addition to gene-splicing entrepreneurs critical in as long as mation is hidden from the public” Physicians in addition to Scientists as long as Responsible Application of Science in addition to Technology “We dem in addition to a global moratorium on the release of genetically engineered organisms in addition to on the use of genetically engineered foods there are reasons to expect potentially serious hazards ”

Gene Transfer Methods Retroviral vectors Lentiviruses Adenovirus Adeno-associated virus (AAV) Other viral vectors Vaccinia – Hepatitis virus Herpes virus – Polio virus Papilloma virus – Sindbis in addition to other RNA viruses Non viral methods Lig in addition to -DNA conjugates – Adenovirus- lig in addition to -DNA Lipofection – Direct DNA injection CaPO4 precipitation – Ribozymes chimeric oligo/gene correction

Problems Delivery of DNA Achieving high level expression Maintaining stable expression Tissue-specific expression in vivo regulation Retroviral Vectors Replace viral genes with therapeutic gene Limited size (<8 kb) Limited cell targets Require dividing cells Specific cellular receptors High efficiency (1 virus/cell) Stable integration into genome Potential as long as insertional mutagenesis Adenovirus Vectors Respiratory diseases in man type 2 in addition to 5 ~36 kb, linear, double str in addition to ed DNA Early genes (E1-E4) Late genes (L1-L5) Replication deficient viruses- Delete E1a in addition to part of E1b grow on Ad trans as long as med cell line (293), which contains E1 region in addition to complements in trans Infect target cell, but no replication Infects broad range of cells liver – CNS lung – endothelial cells muscle – others In addition to being safe in addition to cost-effective, the most important properties of an efficacious gene transfer system will be; 1) target cell selective. 2) transcriptionally competent as long as the desired length of time. 3) available in a highly concentrated active as long as m. 4) immunologically neutral. Gene Therapy Vectors Human Genetic Modifications Somatic or Germline Therapy or Enhancement Figure 13.1 TD Gelehrter, FS Collins, D Ginsburg. Principles of Medical Genetics. 1997. Somatic Gene Therapy Treatment of human diseases by gene transfer transfer of DNA to somatic cells ex vivo or in vivo no effect on germline usually targeted to specific organ/tissue Parisi, Jim Jim Parisi Show  - KNST-AM, The Host www.phwiki.com

Blau &Springer.NEJM 333:1204, 2000. Glycogen storage disease type 1 (GSD-1) Cause: AR deficiency of G6Pase in addition to glucose-6-phosphatase (G6Pase) system glucose-6-phosphate transporter (G6PT) cause GSD-1a in addition to GSD-1b, respectively. Features: growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, in addition to lactic acidemia. GSD-1b also have chronic neutropenia, functional deficiencies of neutrophils in addition to monocytes, recurrent bacterial infections, ulcerations of the oral in addition to intestinal mucosa

Disease Target cells Transfected gene(s) Hemophilia A liver, muscle, Factor VIII Hemophilia B bone marrow cells, fibroblasts Factor IX Familial liver LDL receptor hypercholesterolaemia Severe combined bone marrow cells, T cells Adenosine deaminase (ADA) immunodeficiency Hemoglobinopathies red blood precursor cells a-globin, b-globin Cystic fibrosis lung airway cells CFTR Gaucher disease bone marrow cellsglucocerebrosidase macrophages Cancer tumor cells p53, Rb, interleukins growth-inhibitory genes apoptosis genes ` Good justification as long as using this ex vivo gene therapy approach as long as hemophilia A (factor VIII): – Factor VIII production is not regulated in response to bleeding – Only need to raise levels a little bit, not to 100%, as low levels of the Factor VIII can be beneficial to the patient – Broad therapeutic index of factor VIII minimizes risk of overdose – Delivery of factor VIII into the bloodstream does not require cell-specific expression – NEJM (2001) 341:1735-1742

Key Concerns in addition to Related Ethical Concepts Safety (Nonmaleficence) Efficacy (Beneficence) In as long as med Consent (Autonomy) Allocation of Resources (Justice in addition to Equity) Respect as long as Human Dignity Review: Gene Therapy Germline vs. somatic gene therapy Gene therapy vectors (advantages in addition to disadvantages): Retrovirus Adenovirus Adeno-associated virus (AAV) Non-viral vectors in vivo vs ex vivo gene therapy Current status of human gene therapy experimentation Pharmaceuticals produced by recombinant DNA technology “ if we could make better human beings by knowing how to add genes, why shouldn’t we do it” – James Watson, 3/98

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