Human Gene Therapy: Ethics and Public Policy*

Total Page:16

File Type:pdf, Size:1020Kb

Human Gene Therapy: Ethics and Public Policy* HUMAN G E N E T H E R A P Y 2:115-122 (1991) Mary A n n Liebert, Inc., Publishers Human Gene Therapy: Ethics and Public Policy* LEROY W A L T E R S ABSTRACT The first t h r e e h u m a n gene t r a n s f e r / t h e r a p y clinical p r o t o c o l s a r e n o w u n d e r w a y after h a v i n g b e e n s u b j e c t e d t o a n extensive review process b y t h e Recombinant D N A A d v i s o r y Committee (RAC) a n d i t s H u m a n Gene Therapy S u b c o m m i t t e e . T h e "Points t o C o n s i d e r " d o c u m e n t d e v e l o p e d b y t h e R A C established t h e f r a m e w o r k for e v a l u a t i n g genetic i n t e r v e n t i o n protocols. T h i s r e v i e w process is t a k i n g place in a b r o a d e r social c o n t e x t . Public attitude surveys in t h i s country have indicated a general lack of k n o w l e d g e in t h e area of genetic engineering b u t a n a c c e p t a n c e o f s o m a t i c - c e l l g e n e t h e r a p y a s t r e a t m e n t f o r d i s e a s e . I n t e r n a t i o n a l l y , n u m e r o u s policy s t a t e m e n t s o n h u m a n genetic i n t e r v e n t i o n h a v e b e e n p u b l i s h e d , a l l o f w h i c h s u p p o r t t h e m o r a l legitimacy of s o m a t i c - c e l l g e n e t h e r a p y f o r t h e c u r e o f d i s e a s e . T h e d e b a t e o v e r t h e e t h i c a l i s s u e s r e l a t e d t o s o m a t i c - c e l l g e n e therapy has e v o l v e d over a t e n - y e a r - p e r i o d . T h e time h a s n o w come to b e g i n a f o r m a l public process f o r the ethical a s s e s s m e n t o f g e r m - l i n e g e n e t i c i n t e r v e n t i o n . OVERVIEW SUMMARY human patients s i n c e 1 9 8 0 , a n d the f i r s t p u b l i c l y r e v i e w e d a n d approved h u m a n trials e v e r . An extensive discussion of the ethical issues relating to M y essay will f o c u s first o n the s o c i a l a n d ethical q u e s t i o n s somatic-cell g e n e t h e r a p y h a s b e e n t a k i n g p l a c e f o r a n u m - raised b y these t h r e e p r o p o s a l s a n d b y the r e v i e w process t h a t ber o f y e a r s . A c o n s e n s u s n o w a p p e a r s t o e x i s t t h a t s o m a t i c - was employed to evaluate them. Next, I w i l l consider the cell g e n e therapy for the treatment of serious disease is broader s o c i a l c o n t e x t o f r e s e a r c h o n g e n e t h e r a p y , both in the morally correct. W a l t e r s , f r o m his position as a leading United S t a t e s a n d a b r o a d . F i n a l l y , I will d i s c u s s p o s s i b l e future ethicist w h o has f o l l o w e d t h e field o f g e n e t h e r a p y t h r o u g h - developments, e s p e c i a l l y g e n e t i c i n t e r v e n t i o n s t h a t w o u l d a f f e c t out i t s h i s t o r y , n o w proposes t h a t a f o r m a l p u b l i c d i s c u s s i o n future g e n e r a t i o n s . I n t h i s c o n n e c t i o n , I w i l l r e c o m m e n d that a should b e g i n o n g e r m - l i n e g e n e t h e r a p y . formal public process for t h e ethical a s s e s s m e n t of g e r m - l i n e genetic i n t e r v e n t i o n b e g i n n o w . THE E T H I C A L E V A L U A T I O N O F GENE THERAPY IN T H E U N I T E D S T A T E S , 1 9 6 9 - 1 9 9 0 INTRODUCTION Public discussion of the ethics of human gene therapy goes THREE IMPORTANT MILESTONES in the history of medicine back in t h i s c o u n t r y at l e a s t t o t h e 1 9 6 9 A m e r i c a n Association were p a s s e d b e t w e e n M a y 1989 a n d J a n u a r y 1 9 9 1 . In t h o s e for t h e A d v a n c e m e n t o f S c i e n c e ( A A A S ) m e e t i n g h e l d i n B o s t o n 20 months, t e a m s of researchers at t h e National Institutes o f in l a t e D e c e m b e r . I n a s y m p o s i u m at t h a t m e e t i n g B e r n a r d D a v i s Health ( N I H ) i n i t i a t e d o n e h u m a n gene transfer s t u d y a n d two presented a p a p e r entitled "Threat and Promise in G e n e t i c human g e n e t h e r a p y p r o t o c o l s . T h e s e a r e t h e first s u c h s t u d i e s i n Engineering." T h i s p a p e r w a s l a t e r p u b l i s h e d i n S c i e n c e w i t h t h e Director, Center f o r B i o e t h i c s , K e n n e d y Institute o f E t h i c s , and A s s o c i a t e P r o f e s s o r o f P h i l o s o p h y , G e o r g e t o w n U n i v e r s i t y .
Recommended publications
  • Widespread Gene Transfection Into the Central Nervous System of Primates
    Gene Therapy (2000) 7, 759–763 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15.00 www.nature.com/gt NONVIRAL TRANSFER TECHNOLOGY RESEARCH ARTICLE Widespread gene transfection into the central nervous system of primates Y Hagihara1, Y Saitoh1, Y Kaneda2, E Kohmura1 and T Yoshimine1 1Department of Neurosurgery and 2Division of Gene Therapy Science, Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan We attempted in vivo gene transfection into the central ner- The lacZ gene was highly expressed in the medial temporal vous system (CNS) of non-human primates using the hem- lobe, brainstem, Purkinje cells of cerebellar vermis and agglutinating virus of Japan (HVJ)-AVE liposome, a newly upper cervical cord (29.0 to 59.4% of neurons). Intrastriatal constructed anionic type liposome with a lipid composition injection of an HVJ-AVE liposome–lacZ complex made a similar to that of HIV envelopes and coated by the fusogenic focal transfection around the injection sites up to 15 mm. We envelope proteins of inactivated HVJ. HVJ-AVE liposomes conclude that the infusion of HVJ-AVE liposomes into the containing the lacZ gene were applied intrathecally through cerebrospinal fluid (CSF) space is applicable for widespread the cisterna magna of Japanese macaques. Widespread gene delivery into the CNS of large animals. Gene Therapy transgene expression was observed mainly in the neurons. (2000) 7, 759–763. Keywords: central nervous system; primates; gene therapy; HVJ liposome Introduction ever, its efficiency has not been satisfactory in vivo. Recently HVJ-AVE liposome, a new anionic-type lipo- Despite the promising results in experimental animals, some with the envelope that mimics the human immuno- gene therapy has, so far, not been successful in clinical deficiency virus (HIV), has been developed.13 Based upon 1 situations.
    [Show full text]
  • Recombinant DNA and Elements Utilizing Recombinant DNA Such As Plasmids and Viral Vectors, and the Application of Recombinant DNA Techniques in Molecular Biology
    Fact Sheet Describing Recombinant DNA and Elements Utilizing Recombinant DNA Such as Plasmids and Viral Vectors, and the Application of Recombinant DNA Techniques in Molecular Biology Compiled and/or written by Amy B. Vento and David R. Gillum Office of Environmental Health and Safety University of New Hampshire June 3, 2002 Introduction Recombinant DNA (rDNA) has various definitions, ranging from very simple to strangely complex. The following are three examples of how recombinant DNA is defined: 1. A DNA molecule containing DNA originating from two or more sources. 2. DNA that has been artificially created. It is DNA from two or more sources that is incorporated into a single recombinant molecule. 3. According to the NIH guidelines, recombinant DNA are molecules constructed outside of living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or molecules that result from their replication. Description of rDNA Recombinant DNA, also known as in vitro recombination, is a technique involved in creating and purifying desired genes. Molecular cloning (i.e. gene cloning) involves creating recombinant DNA and introducing it into a host cell to be replicated. One of the basic strategies of molecular cloning is to move desired genes from a large, complex genome to a small, simple one. The process of in vitro recombination makes it possible to cut different strands of DNA, in vitro (outside the cell), with a restriction enzyme and join the DNA molecules together via complementary base pairing. Techniques Some of the molecular biology techniques utilized during recombinant DNA include: 1.
    [Show full text]
  • REVIEW Gene Therapy
    Leukemia (2001) 15, 523–544 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu REVIEW Gene therapy: principles and applications to hematopoietic cells VFI Van Tendeloo1,2, C Van Broeckhoven2 and ZN Berneman1 1Laboratory of Experimental Hematology, University of Antwerp (UIA), Antwerp University Hospital (UZA), Antwerp; and 2Laboratory of Molecular Genetics, University of Antwerp (UIA), Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Antwerp, Belgium Ever since the development of technology allowing the transfer Recombinant viral vectors of new genes into eukaryotic cells, the hematopoietic system has been an obvious and desirable target for gene therapy. The last 10 years have witnessed an explosion of interest in this Biological gene transfer methods make use of modified DNA approach to treat human disease, both inherited and acquired, or RNA viruses to infect the cell, thereby introducing and with the initiation of multiple clinical protocols. All gene ther- expressing its genome which contains the gene of interest (= apy strategies have two essential technical requirements. ‘transduction’).1 The most commonly used viral vectors are These are: (1) the efficient introduction of the relevant genetic discussed below. In each case, recombinant viruses have had material into the target cell and (2) the expression of the trans- gene at therapeutic levels. Conceptual and technical hurdles the genes encoding essential replicative and/or packaging pro- involved with these requirements are still the objects of active teins replaced by the gene of interest. Advantages and disad- research. To date, the most widely used and best understood vantages of each recombinant viral vector are summarized in vectors for gene transfer in hematopoietic cells are derived Table 1.
    [Show full text]
  • Gene Therapy and Genetic Engineering: Frankenstein Is Still a Myth, but It Should Be Reread Periodically
    Indiana Law Journal Volume 48 Issue 4 Article 2 Summer 1973 Gene Therapy and Genetic Engineering: Frankenstein is Still a Myth, but it Should be Reread Periodically George A. Hudock Indiana University - Bloomington Follow this and additional works at: https://www.repository.law.indiana.edu/ilj Part of the Genetics and Genomics Commons Recommended Citation Hudock, George A. (1973) "Gene Therapy and Genetic Engineering: Frankenstein is Still a Myth, but it Should be Reread Periodically," Indiana Law Journal: Vol. 48 : Iss. 4 , Article 2. Available at: https://www.repository.law.indiana.edu/ilj/vol48/iss4/2 This Article is brought to you for free and open access by the Law School Journals at Digital Repository @ Maurer Law. It has been accepted for inclusion in Indiana Law Journal by an authorized editor of Digital Repository @ Maurer Law. For more information, please contact [email protected]. GENE THERAPY AND GENETIC ENGINEERING: FRANKENSTEIN IS STILL A MYTH, BUT IT SHOULD BE REREAD PERIODICALLY GEORGE A. HUDOCKt Biotechnology and the law are far removed from each other as disciplines of human intellect. Yet the law and my own discipline, genetics, have come together in many courtrooms concerning such matters as paternity, and they will continue to intersect with increasing frequency as the visions of 100 years ago become the reality of today. This article examines the implications of recent research for human genetic therapy and genetic engineering, and suggests some guidelines for legal regulation of genetic technology. The following discussion derives from three premises which I view as basic: (1) that which is currently possible in genetic engineering, and in fact has already been done, is generally underestimated; (2) what may be possible in the near future is quite commonly overesti- mated; (3) regulation of the application of genetic technology is possible and will not be overwhelmingly complicated.
    [Show full text]
  • Intramuscular Electroporation Delivery of IFN- Gene Therapy for Inhibition of Tumor Growth Located at a Distant Site
    Gene Therapy (2001) 8, 400–407 2001 Nature Publishing Group All rights reserved 0969-7128/01 $15.00 www.nature.com/gt RESEARCH ARTICLE Intramuscular electroporation delivery of IFN-␣ gene therapy for inhibition of tumor growth located at a distant site S Li, X Zhang, X Xia, L Zhou, R Breau, J Suen and E Hanna Department of Otolaryngology/Head and Neck Surgery, University of Arkansas School of Medicine, 4001 W Capital Avenue, Little Rock, AR 72205, USA Although electroporation has been shown in recent years to 2 or endostatin gene, also delivered by electro-injection. The be a powerful method for delivering genes to muscle, no increased therapeutic efficacy was associated with a high gene therapy via electro-injection has been studied for the level and extended duration of IFN-␣ expression in muscle treatment of tumors. In an immunocompetent tumor-bearing and serum. We also discovered that the high level of IFN-␣ murine model, we have found that delivery of a low dose of expression correlated with increased expression levels of reporter gene DNA (10 ␮g) to muscle via electroporation the antiangiogenic genes IP-10 and Mig in local tumor under specific pulse conditions (two 25-ms pulses of 375 tissue, which may have led to the reduction of blood vessels V/cm) increased the level of gene expression by two logs of observed at the local tumor site. Delivery of increasing doses magnitude. Moreover, administration of 10 ␮g of interferon (10–100 ␮g) of IFN-␣ plasmid DNA by injection alone did (IFN)-␣ DNA plasmid using these parameters once a week not increase antitumor activity, whereas electroporation for 3 weeks increased the survival time and reduced squam- delivery of increasing doses (10–40 ␮g) of IFN-␣ plasmid ous cell carcinoma (SCC) growth at a distant site in the DNA did increase the survival time.
    [Show full text]
  • New Techniques of Genetic Engineering
    March 2016 New techniques of genetic engineering Why EU GMO law must be fully applied to the so-called ‘New Plant Breeding Techniques’ The European Commission is considering whether genetically modified organisms (GMOs) that have been produced through a range of new techniques should be excluded from the European Union’s GMO regulations. Biotechnology companies want to apply these techniques to engineer plants and animals for use in industrial food, biomass and biofuel production. They argue that these new methods to directly modify the genetic make-up of living organisms fall outside the scope of EU GMO regulations. This would mean that there is no risk assessment, labelling and monitoring of GM organisms produced by the new techniques and their derived products. The Commission has announced that it will present a legal analysis on the matter by the end of March 2016. The new GMOs present a real risk to the environment and human health. Legal analysis shows that they are covered by EU GMO law. If they were to escape EU regulations, any potential negative effects on food, feed or environmental safety would go unchecked. European consumers, farmers and breeders would have no way to avoid GMOs. The Commission should leave no doubt that all products of genetic engineering are subject to EU GMO law which requires rigorous risk assessment, detectability and labelling. 1 Which techniques are we talking about? The biotechnology industry and the European Commission use the term ‘New Plant Breeding Techniques’ to refer to a diverse set of genetic
    [Show full text]
  • Drawing the Line: Disability, Genetic Intervention and Bioethics
    laws Article Drawing the Line: Disability, Genetic Intervention and Bioethics Adam Conti Graduate student, Melbourne Law School, University of Melbourne, 185 Pelham St., Carlton, VIC 3053, Australia; [email protected] Received: 2 June 2017; Accepted: 10 July 2017; Published: 17 July 2017 Abstract: Meteoric scientific advances in genetic technologies with the potential for human gene editing intervention pose tremendous legal, medical, social, ethical and moral issues for society as a whole. Persons with disabilities in particular have a significant stake in determining how these technologies are governed at the international, domestic and individual levels in the future. However, the law cannot easily keep up with the rate of scientific progression. This paper aims to posit a methodology of reform, based on a core value of human dignity, as the optimal course of action to ensure that the interests of persons with disabilities, other possibly marginalised groups, and the scientific community, are balanced fairly. The paper critically analyses the current law and varying bioethical perspectives to ultimately conclude that a clear principled approach toward open discussion and consensus is of paramount importance to have any chance of devising an effective regulatory regime over human gene editing technology. Keywords: disability; human rights; genetics; gene editing; bioethics; governance; human dignity; eugenics; germline; Convention on the Rights of Persons with Disabilities The true good is in the different, not the same (Menand 2004). 1. Introduction Popular, professional and scholarly interest in genetics and their influence on human variability, behaviour and development has grown exponentially in recent years. In no small part has this interest been bolstered by mainstream media coverage of large-scale collaborative scientific initiatives like the Human Genome Project, which endeavoured to identify and map the human genome and determine the sequence of nucleotide base pairs that make up our DNA.
    [Show full text]
  • HD-Guidance Document Gene Therapy/GMO Environmental Data
    HD-Guidance document Gene Therapy/GMO Environmental Data Guidance document for the compilation of the documentation on possible risks for humans and the environment in support of applications for the authorisation to carry out clinical trials of somatic gene therapy and with medicines containing genetically modified microorganisms (environmental data) In accordance with Articles 22, 35 and Annex 4 ClinO by Swiss Agency for Therapeutic Products (Swissmedic), Federal Office for Public Health (FOPH), Federal Office for the Environment (FOEN), Swiss Expert Committee for Biosafety (SECB) Contents 1 Summary .....................................................................................................................................2 2 Decision tree regarding the compilation of environmental data documentation ................... 3 3 Preliminary remarks / legal basis ..............................................................................................4 4 Definition of genetically modified microorganisms (GMOs) ....................................................5 5 Environmental data documentation ..........................................................................................5 5.1 General information ............................................................................................................................... 5 5.2 Determining and evaluating the risks for humans and the environment (risk assessment) ......... 6 5.2.1 Guidance for the risk assessment ...................................................................................................
    [Show full text]
  • Genetic Engineering & Genetically Modified Organisms
    Genetic Engineering & Genetically Modified Organisms: Forming Informed Opinions By Smith, Lisa Scientific Theme(s): Science and Technology *Relationships among science, technology, and society Grade Level(s): 6-8 Lesson Duration: Designed for one 70 minute lesson Overview This lesson provides students an introduction to genetic engineering and genetically modified organisms, and raises student awareness of the potential Bias of availaBle information and the importance of forming informed, defendaBle opinions regarding controversial topics in science. The lesson was designed as an introduction for students to the genetic engineering and genetically modified organisms in preparation for a two-week research project exploring GMO topics, culminating with student presentations giving their opinions on the topics. Objectives Students will: 1. Define the term, ‘Biotechnology’. 2. Understand the difference Between selective Breeding and genetic engineering. 3. Identify different applications of genetic engineering, and recognize that all genetically engineered organisms are genetically modified organisms (GMOs). 4. Recognize Bias in print media, and to Be aware of the need to identify sources. 5. Understand the importance of forming informed, defendaBle opinions. Grade Level Expectations (GLEs) Addressed Science as Inquiry and Process [7] SA2.1 identifying and evaluating the sources used to support scientific statements Science and Technology [7] SE1.1 descriBing how puBlic policy affects the student’s life (e.g., puBlic waste disposal) [7] SE3.1 recognizing the effects of a past scientific discovery, invention, or scientific Breakthrough (e.g., DDT, internal comBustion engine) Required BacKground This lesson builds upon concepts covered in previous lessons on DNA, genes, and heredity. Students should have a solid understanding of the Basics of these concepts, including the idea that DNA is the “Blueprint” of life, that genes are coding regions of DNA, and that traits encoded By genes can Be inherited.
    [Show full text]
  • Askbio Announces IND for LION-101, a Novel Investigational AAV Gene
    AskBio Announces IND for LION-101, a Novel Investigational AAV Gene Therapy for the Treatment of Limb-Girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9), Cleared to Proceed by U.S. FDA -- LGMD2I/R9 is a Rare Form of Muscular Dystrophy with No Approved Therapies – -- First-in-Human Phase 1/2 Clinical Study Expected to Begin Dosing in 1H 2022 – Research Triangle Park, N.C. – May 25, 2021 – Asklepios BioPharmaceutical, Inc. (AskBio), a wholly owned and independently operated subsidiary of Bayer AG, announced that the U.S. Food & Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for LION-101 to proceed in a Phase 1/2 clinical study. LION-101 is a novel recombinant adeno-associated virus (rAAV) based vector being developed as a one-time intravenous infusion for the treatment of patients with Limb-Girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9). LION-101 will be evaluated in a first-in-human Phase 1/2 multicenter study to evaluate a single intravenous (IV) infusion in adult and adolescent subjects with genotypically confirmed LGMD2I/R9. AskBio plans to initiate dosing for the LION-101 Phase 1/2 clinical study in the first half of 2022. “In preclinical mouse models, LION-101 therapy demonstrated both dose-dependent efficacy and tolerability, providing a clear approach to study this novel AAV vector in first-in-human trials,” said Katherine High, MD, President, Therapeutics, AskBio. “Currently there are no approved therapies for LGMD2I/R9, and with limited treatment options that only address symptoms of the disease, the patient burden is profound.
    [Show full text]
  • Human Gene Therapy (Part 6 Of
    Background on Genetic Diseases 13 Background on genetic diseases Chromosomes and inheritance ual. The relative importance of genetic and envi- ronmental influences varies in both patients and Higher organisms package their DNA into seg- diseases. Some medical conditions, such as auto- ments called chromosomes. Each chromosome is mobile accidents or war wounds, may have large composed of one very long stretch of DNA that environmental and very small genetic contribu- is bound to various proteins and other molecules. tions. Most diseases have a mixture of genetic and There are two copies of each of 22 chromosomes environmental contributions (Harsanyi, 1981). In in the cells of a human. In addition, there are two several disorders, such as Huntington or Tay- sex chromosomes. Females have two ‘(X” chromo- Sachs diseases, the influence of a single gene is somes and males have one “X” and one “Y. ” In nor- so large that the disorders are called genetic mal human cells, therefore, there are 46 chromo- diseases. somes: 2 sex chromosomes and 2 copies of each of 22 other chromosomes (these non-sex chromo- somes are called autosomes). SINGLE GENE TRAITS, OR MENDELIAN TRAITS When traits or diseases are primarily deter- The 46 discrete aggregates of DNA and attached mined by a single gene, they obey the relatively protein that comprise the chromosomes are main- simple laws of inheritance first specified by tained inside the nucleus of somatic cells. In germ Gregor Mendel, a monk who lived in the last cen- cells, in contrast, a specialized phenomenon called tury and whose interests in agriculture led him meiosis takes place.
    [Show full text]
  • The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases
    International Journal of Molecular Sciences Review The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases Lyes Toualbi 1,2, Maria Toms 1,2 and Mariya Moosajee 1,2,3,4,* 1 UCL Institute of Ophthalmology, London EC1V 9EL, UK; [email protected] (L.T.); [email protected] (M.T.) 2 The Francis Crick Institute, London NW1 1AT, UK 3 Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK 4 Great Ormond Street Hospital for Children NHS Found Trust, London WC1N 3JH, UK * Correspondence: [email protected]; Tel.: +44-207-608-6971 Abstract: Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progres- sive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. How- ever, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Here, we review the advances in non-viral gene augmentation strategies, such as the use of plasmids with minimal bacterial backbones and scaffold/matrix attachment region (S/MAR) sequences, that have the capability to overcome these weaknesses by accommodating genes of any size and maintaining episomal transgene expression with a lower risk of eliciting an immune response. Low retinal transfection rates remain a limita- tion, but various strategies, including coupling the DNA with different types of chemical vehicles (nanoparticles) and the use of electrical methods such as iontophoresis and electrotransfection to aid Citation: Toualbi, L.; Toms, M.; Moosajee, M.
    [Show full text]