Ethical Perspectives Address correspondence to Dr Peter B. Kang, Division of Pediatric Neurology, University of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610, [email protected]. Relationship Disclosure: Dr Kang has served as an officer and trustee of the Massachusetts Medical Society and received grant funding from Isis Pharmaceuticals, Inc; the Muscular Dystrophy Association; and the NIH. Dr Kang has received honoraria from the AAN, the American College of Medical Genetics, Boston Children’s Hospital, Brooks Publishing, the Fondazione Cariplo, the Massachusetts Medical Society, the US Department of Health and Human ServicesVHealth Resources and Services Administration’s National Vaccine Injury Compensation Program, and the US Department of Veterans Affairs. Unlabeled Use of Products/Investigational Use Disclosure: Dr Kang discusses therapies for the treatment of muscle disease, all of which are unlabeled. * 2013, American Academy of Neurology.
The New Frontier of Genetically Targeted Therapies for Muscle Disease Peter B. Kang, MD
ABSTRACT This article presents the case of a 5-year-old boy with Duchenne muscular dystrophy who is eligible to enroll in a clinical trial of gene therapy for this disorder. His parents are grappling with the decision about whether to enroll him. Among the issues under consideration are the potential risks and benefits to him, the costs of participating (because frequent, partially reimbursed travel is involved), and the potential cost savings of receiving this treatment on a research basis rather than as a clinically approved therapy. His parents seek the advice of his pediatric neurologist. After careful consideration of the various factors above, the pediatric neurologist explains to the family that participating in the trial is ethically permissible but that, given the uncertain benefits and potential for substantial expenses without benefit to the child, participation should not be regarded as ethically obligatory. Continuum (Minneap Minn) 2013;19(6):1698–1702.
Case A 5-year-old boy in a pediatric neuromuscular clinic has recently been diagnosed with Duchenne muscular dystrophy based on clinical presentation, serum creatine kinase levels, and a clearly pathogenic genetic mutation. He has some difficulties with stairs and running, but ambulation is reasonably intact at this stage of his illness. Soon after diagnosis, his parents hear of a clinical trial of gene therapy for Duchenne muscular dystrophy that is open for enrollment. They contact the study coordinator and, after several discussions, find out that their son is eligible for enrollment. The study involves systemic delivery, via IV injection, of a mini-dystrophin gene using an adeno-associated virus vector. The research center is located in a different state, and participation requires approximately six round trips via airplane for the boy and at least one parent. The hotel stays will be reimbursed, but airfares will not. The boy’s father is currently unemployed; the family relies on his mother’s job as a retail store manager for income and health insurance. Participation would be a financial burden on them, and it is not guaranteed that this therapy would be covered by their health insurance if it is approved in the future by the US Food and Drug Administration (FDA). The parents seek advice from the boy’s pediatric neurologist.
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
December 2013
DISCUSSION The discovery of the gene for Duchenne muscular dystrophy in 19861,2 led to an explosion of research into genetically targeted therapies for this disease and many other inherited disorders. Some impressive advances have been made since then, including enzyme replacement therapy for the infantile3Y6 and lateonset7Y9 forms of Pompe disease, another inherited muscle disease. Recent human data on antisense oligonucleotide therapy (exon skipping) for Duchenne muscular dystrophy have been promising, and approval by the FDA is pending. However, while important medical and surgical therapies exist for Duchenne muscular dystrophy, a definitive intervention that dramatically alters the natural history of this disease remains elusive, and thus the issue of whether to participate in clinical trials for novel therapeutic approaches will recur many times in the coming years. Genetically targeted approaches that may apply to Duchenne muscular dystrophy include antisense oligonucleotide therapy, gene therapy, and stem cell therapy.10 A consideration of potential benefits in the current case scenario includes the receipt of a potentially efficacious treatment before the FDA approval process (which can be quite lengthy in some cases), without charge for the treatment during the study period. The potential benefit is substantial, given the paucity of currently available therapies for Duchenne muscular dystrophy and the inexorable course that leads to loss of ambulation during late childhood or early adolescence. Genetically targeted therapies are expected to be costly, especially when ongoing treatments are needed, as the example of enzyme replacement therapy for Pompe disease has shown.11 Supporters of these interventions argue that although the cost of the therapies is high for individual patients, the targeted diseases are typically rare ones, minimizing the overall financial burden to society as a whole compared to the cost of a new drug for common diseases such as hypertension or diabetes. Therefore the financial burden to society as a whole, via private insurance companies or governmentsponsored entities, has been small. However, this argument may begin to lose some of its force as an increasing number of such therapies are brought online and the collective costs of all of these interventions increase.11 New costs in the health care system will be increasingly scrutinized in the years to come,12 and third-party payers may resist high reimbursements for these products in the future. The potential risks of participation in clinical trials of gene therapy have changed over the years. The low point for gene therapy was in 1999, when Jesse Gelsinger, a subject in a human gene therapy trial, died as a result of a massive immune response to the adenoviral vector that was used.13 That event raised a number of scientific and ethical questions and was a painful learning experience for all scientists and physicians working in the field.14 Another setback was experienced in the field several years later when several patients treated with gene therapy for severe combined immunodeficiency disease (SCID) developed leukemia.15,16 Many advances have occurred since these tragic events, and gene therapy has now been found to be safe and efficacious for the treatment of several diseases, including adrenoleukodystrophy,17 "-thalassemia,18 and Leber congenital amaurosis.19,20 One major advance has been the transition from using adenoviral vectors to smaller, less immunogenic vectors such as the adeno-associated virus.21,22 The use of large mammal experiments in preclinical Continuum (Minneap Minn) 2013;19(6):1698–1702
www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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Genetically Targeted Therapies
research has also expanded. In particular, it is becoming more common to use a golden retriever model of Duchenne muscular dystrophy to test potential new therapies.23 Lastly, biomedical scientists have learned a great deal from (and since) the Jesse Gelsinger case and the SCID/leukemia events. Many human gene therapy trials have been conducted over the past decade without a recurrence of such negative outcomes. Human subjects should be made aware of these earlier events during the consent process for a gene therapy trial but should also be reassured of the positive developments and numerous human studies that have been conducted since then with excellent patient tolerance and some major breakthroughs. The most likely current risk is that the intervention will not work. A human trial of gene therapy for Duchenne muscular dystrophy identified an immune response to the donor dystrophin protein, a complication that may limit the efficacy of this intervention as currently designed.24 Therefore, the family should consider the potential harms to both the patient and the family from participation in a clinical trial that is unsuccessful, including financial burdens, lost time at work, and recurrent family separations. Some families are concerned about eligibility for future trials if they choose to enroll in a particular study. Inclusion and exclusion criteria vary by study, but given the limited population available for enrollment, investigators tend to be as inclusive as possible regarding such criteria. A small risk also exists to not participating in the clinical trial. In the case at hand, if the family declines to participate, the disease will likely progress, and if the therapy is found to benefit only ambulatory patients with Duchenne muscular dystrophy, the patient will miss a window of opportunity that may never open again. This is a fear that lurks in the minds of many parents of affected boys, but such a risk is difficult to quantify. The distinction between consent and assent is important, as participants in studies of Duchenne muscular dystrophy are often young, many with varying degrees of cognitive delay. The concept of assent means that children and adolescents should, to the extent that their developmental level permits, be included in explanations of research studies and participate in the decision about whether to enroll.25 Children should express a developmentally appropriate level of willingness to participate. Above a certain threshold age, which varies by study and institution, children and adolescents may even have the opportunity to sign assent lines in informed consent documents to supplement their parents’ or guardians’ consent signatures. However, even those who are younger than the threshold age should be informed about the study. During the consent process, the physician should take the initiative to raise financial issues and remind the parents that bankrupting the family in the pursuit of unproven therapies may not be in the best interest of the child, and that consideration of costs is a legitimate factor to be taken into account. In cases in which a promising therapy is offered, a family may feel that they have no choice but to enroll their child, regardless of the burdens that participation may place on the family and of the uncertainty of benefit. A family may harbor feelings of guilt regarding their child’s condition that are clearly unjustified but may overwhelm rational judgments in such deliberations. Affected children and their families should be counseled to weigh both potential benefits and risks,
1700
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
December 2013
including expenses, when deciding whether to enroll in a study that may impose a financial toll on the family. The conflict of interest issue is important.26 Conflicts of interest are not inherently wrong, but they should be minimized, controlled, and disclosed. Members of the investigator’s team are obliged to disclose potential conflicts regarding the investigational therapy. These may include situations such as an investigator who receives research funding to direct the local site for a multicenter clinical trial or who holds an interest in a biotechnology firm involved in the study and thus may stand to profit from a successful outcome. Such relationships must be disclosed to the families and are now required to be included in written consent forms, but families should feel comfortable asking investigators directly about such conflicts. Most families will be comfortable with reasonable conflicts of interest if these are disclosed properly. In conclusion, when a pediatric neurologist or other physician involved in the care of a child with an inherited muscle disease such as Duchenne muscular dystrophy is asked about potential participation in a clinical trial of a sophisticated genetically targeted therapy, the physician should explain to parents that their responsibility is to ascertain the balance of risks and benefits of participation as they relate to the interests of the child. The physician should provide the families with a framework to use when considering the risks and benefits of enrollment, pointing out the ethical relevance of financial considerations and conflicts of interest to the decision at hand. Lastly, if the physician has an informed opinion on the scientific rationale of the therapy, it would be reasonable to air such thoughts, with the disclosure of any conflicts of interest that may exist. In most cases, participation in such studies can be determined to be ethically permissible but not ethically obligatory. REFERENCES 1. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987;51(6):919Y928. 2. Monaco AP, Neve RL, Colletti-Feener C, et al. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 1986;323(6089):646Y650. 3. Ansong AK, Li JS, Nozik-Grayck E, et al. Electrocardiographic response to enzyme replacement therapy for Pompe disease. Genet Med 2006;8(5):297Y301. 4. Chen LR, Chen CA, Chiu SN, et al. Reversal of cardiac dysfunction after enzyme replacement in patients with infantile-onset Pompe disease. J Pediatr 2009;155(2):271Y275.e272. 5. Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68(2):99Y109. 6. Van den Hout JM, Kamphoven JH, Winkel LP, et al. Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 2004;113(5): e448Ye457. 7. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 2010;362(15):1396Y1406. 8. Strothotte S, Strigl-Pill N, Grunert B, et al. Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial. J Neurol 2010;257(1):91Y97. 9. Cupler EJ, Berger KI, Leshner RT, et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve 2012;45(3):319Y333. 10. Liew WK, Kang PB. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. Ther Adv Neurol Disord 2013;6(3):147Y160.
Continuum (Minneap Minn) 2013;19(6):1698–1702
www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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11. Murphy SM, Puwanant A, Griggs RC; Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol 2012;72(4):481Y490. 12. Neumann PJ. What we talk about when we talk about health care costs. N Engl J Med 2012;366(7):585Y586. 13. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80(1Y2):148Y158. 14. Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab 2009;96(4):151Y157. 15. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348(3):255Y256. 16. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302(5644):415Y419. 17. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009;326(5954):818Y823. 18. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 2010;467(7313):318Y322. 19. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Vision 1 year after gene therapy for Leber’s congenital amaurosis. N Engl J Med 2009;361(7):725Y727. 20. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012;130(1):9Y24. 21. Pacak CA, Byrne BJ. AAV vectors for cardiac gene transfer: experimental tools and clinical opportunities. Mol Ther 2011;19(9):1582Y1590. 22. Pacak CA, Mah CS, Thattaliyath BD, et al. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006;99(4):e3Ye9. 23. Kornegay JN, Bogan JR, Bogan DJ, et al. Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. Mamm Genome 2012;23(1Y2):85Y108. 24. Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med 2010;363(15):1429Y1437. 25. Lee KJ, Havens PL, Sato TT, et al. Assent for treatment: clinician knowledge, attitudes, and practice. Pediatrics 2006;118(2):723Y730. 26. Martin JB. The pervasive influence of conflicts of interest: a personal perspective. Neurology 2010;74(24):2016Y2021.
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December 2013
The New Frontier of Genetically Targeted Therapies for Muscle Disease Peter B. Kang, MD
ABSTRACT This article presents the case of a 5-year-old boy with Duchenne muscular dystrophy who is eligible to enroll in a clinical trial of gene therapy for this disorder. His parents are grappling with the decision about whether to enroll him. Among the issues under consideration are the potential risks and benefits to him, the costs of participating (because frequent, partially reimbursed travel is involved), and the potential cost savings of receiving this treatment on a research basis rather than as a clinically approved therapy. His parents seek the advice of his pediatric neurologist. After careful consideration of the various factors above, the pediatric neurologist explains to the family that participating in the trial is ethically permissible but that, given the uncertain benefits and potential for substantial expenses without benefit to the child, participation should not be regarded as ethically obligatory. Continuum (Minneap Minn) 2013;19(6):1698–1702.
Case A 5-year-old boy in a pediatric neuromuscular clinic has recently been diagnosed with Duchenne muscular dystrophy based on clinical presentation, serum creatine kinase levels, and a clearly pathogenic genetic mutation. He has some difficulties with stairs and running, but ambulation is reasonably intact at this stage of his illness. Soon after diagnosis, his parents hear of a clinical trial of gene therapy for Duchenne muscular dystrophy that is open for enrollment. They contact the study coordinator and, after several discussions, find out that their son is eligible for enrollment. The study involves systemic delivery, via IV injection, of a mini-dystrophin gene using an adeno-associated virus vector. The research center is located in a different state, and participation requires approximately six round trips via airplane for the boy and at least one parent. The hotel stays will be reimbursed, but airfares will not. The boy’s father is currently unemployed; the family relies on his mother’s job as a retail store manager for income and health insurance. Participation would be a financial burden on them, and it is not guaranteed that this therapy would be covered by their health insurance if it is approved in the future by the US Food and Drug Administration (FDA). The parents seek advice from the boy’s pediatric neurologist.
1698
www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
December 2013
DISCUSSION The discovery of the gene for Duchenne muscular dystrophy in 19861,2 led to an explosion of research into genetically targeted therapies for this disease and many other inherited disorders. Some impressive advances have been made since then, including enzyme replacement therapy for the infantile3Y6 and lateonset7Y9 forms of Pompe disease, another inherited muscle disease. Recent human data on antisense oligonucleotide therapy (exon skipping) for Duchenne muscular dystrophy have been promising, and approval by the FDA is pending. However, while important medical and surgical therapies exist for Duchenne muscular dystrophy, a definitive intervention that dramatically alters the natural history of this disease remains elusive, and thus the issue of whether to participate in clinical trials for novel therapeutic approaches will recur many times in the coming years. Genetically targeted approaches that may apply to Duchenne muscular dystrophy include antisense oligonucleotide therapy, gene therapy, and stem cell therapy.10 A consideration of potential benefits in the current case scenario includes the receipt of a potentially efficacious treatment before the FDA approval process (which can be quite lengthy in some cases), without charge for the treatment during the study period. The potential benefit is substantial, given the paucity of currently available therapies for Duchenne muscular dystrophy and the inexorable course that leads to loss of ambulation during late childhood or early adolescence. Genetically targeted therapies are expected to be costly, especially when ongoing treatments are needed, as the example of enzyme replacement therapy for Pompe disease has shown.11 Supporters of these interventions argue that although the cost of the therapies is high for individual patients, the targeted diseases are typically rare ones, minimizing the overall financial burden to society as a whole compared to the cost of a new drug for common diseases such as hypertension or diabetes. Therefore the financial burden to society as a whole, via private insurance companies or governmentsponsored entities, has been small. However, this argument may begin to lose some of its force as an increasing number of such therapies are brought online and the collective costs of all of these interventions increase.11 New costs in the health care system will be increasingly scrutinized in the years to come,12 and third-party payers may resist high reimbursements for these products in the future. The potential risks of participation in clinical trials of gene therapy have changed over the years. The low point for gene therapy was in 1999, when Jesse Gelsinger, a subject in a human gene therapy trial, died as a result of a massive immune response to the adenoviral vector that was used.13 That event raised a number of scientific and ethical questions and was a painful learning experience for all scientists and physicians working in the field.14 Another setback was experienced in the field several years later when several patients treated with gene therapy for severe combined immunodeficiency disease (SCID) developed leukemia.15,16 Many advances have occurred since these tragic events, and gene therapy has now been found to be safe and efficacious for the treatment of several diseases, including adrenoleukodystrophy,17 "-thalassemia,18 and Leber congenital amaurosis.19,20 One major advance has been the transition from using adenoviral vectors to smaller, less immunogenic vectors such as the adeno-associated virus.21,22 The use of large mammal experiments in preclinical Continuum (Minneap Minn) 2013;19(6):1698–1702
www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1699
Genetically Targeted Therapies
research has also expanded. In particular, it is becoming more common to use a golden retriever model of Duchenne muscular dystrophy to test potential new therapies.23 Lastly, biomedical scientists have learned a great deal from (and since) the Jesse Gelsinger case and the SCID/leukemia events. Many human gene therapy trials have been conducted over the past decade without a recurrence of such negative outcomes. Human subjects should be made aware of these earlier events during the consent process for a gene therapy trial but should also be reassured of the positive developments and numerous human studies that have been conducted since then with excellent patient tolerance and some major breakthroughs. The most likely current risk is that the intervention will not work. A human trial of gene therapy for Duchenne muscular dystrophy identified an immune response to the donor dystrophin protein, a complication that may limit the efficacy of this intervention as currently designed.24 Therefore, the family should consider the potential harms to both the patient and the family from participation in a clinical trial that is unsuccessful, including financial burdens, lost time at work, and recurrent family separations. Some families are concerned about eligibility for future trials if they choose to enroll in a particular study. Inclusion and exclusion criteria vary by study, but given the limited population available for enrollment, investigators tend to be as inclusive as possible regarding such criteria. A small risk also exists to not participating in the clinical trial. In the case at hand, if the family declines to participate, the disease will likely progress, and if the therapy is found to benefit only ambulatory patients with Duchenne muscular dystrophy, the patient will miss a window of opportunity that may never open again. This is a fear that lurks in the minds of many parents of affected boys, but such a risk is difficult to quantify. The distinction between consent and assent is important, as participants in studies of Duchenne muscular dystrophy are often young, many with varying degrees of cognitive delay. The concept of assent means that children and adolescents should, to the extent that their developmental level permits, be included in explanations of research studies and participate in the decision about whether to enroll.25 Children should express a developmentally appropriate level of willingness to participate. Above a certain threshold age, which varies by study and institution, children and adolescents may even have the opportunity to sign assent lines in informed consent documents to supplement their parents’ or guardians’ consent signatures. However, even those who are younger than the threshold age should be informed about the study. During the consent process, the physician should take the initiative to raise financial issues and remind the parents that bankrupting the family in the pursuit of unproven therapies may not be in the best interest of the child, and that consideration of costs is a legitimate factor to be taken into account. In cases in which a promising therapy is offered, a family may feel that they have no choice but to enroll their child, regardless of the burdens that participation may place on the family and of the uncertainty of benefit. A family may harbor feelings of guilt regarding their child’s condition that are clearly unjustified but may overwhelm rational judgments in such deliberations. Affected children and their families should be counseled to weigh both potential benefits and risks,
1700
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
December 2013
including expenses, when deciding whether to enroll in a study that may impose a financial toll on the family. The conflict of interest issue is important.26 Conflicts of interest are not inherently wrong, but they should be minimized, controlled, and disclosed. Members of the investigator’s team are obliged to disclose potential conflicts regarding the investigational therapy. These may include situations such as an investigator who receives research funding to direct the local site for a multicenter clinical trial or who holds an interest in a biotechnology firm involved in the study and thus may stand to profit from a successful outcome. Such relationships must be disclosed to the families and are now required to be included in written consent forms, but families should feel comfortable asking investigators directly about such conflicts. Most families will be comfortable with reasonable conflicts of interest if these are disclosed properly. In conclusion, when a pediatric neurologist or other physician involved in the care of a child with an inherited muscle disease such as Duchenne muscular dystrophy is asked about potential participation in a clinical trial of a sophisticated genetically targeted therapy, the physician should explain to parents that their responsibility is to ascertain the balance of risks and benefits of participation as they relate to the interests of the child. The physician should provide the families with a framework to use when considering the risks and benefits of enrollment, pointing out the ethical relevance of financial considerations and conflicts of interest to the decision at hand. Lastly, if the physician has an informed opinion on the scientific rationale of the therapy, it would be reasonable to air such thoughts, with the disclosure of any conflicts of interest that may exist. In most cases, participation in such studies can be determined to be ethically permissible but not ethically obligatory. REFERENCES 1. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987;51(6):919Y928. 2. Monaco AP, Neve RL, Colletti-Feener C, et al. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 1986;323(6089):646Y650. 3. Ansong AK, Li JS, Nozik-Grayck E, et al. Electrocardiographic response to enzyme replacement therapy for Pompe disease. Genet Med 2006;8(5):297Y301. 4. Chen LR, Chen CA, Chiu SN, et al. Reversal of cardiac dysfunction after enzyme replacement in patients with infantile-onset Pompe disease. J Pediatr 2009;155(2):271Y275.e272. 5. Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68(2):99Y109. 6. Van den Hout JM, Kamphoven JH, Winkel LP, et al. Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 2004;113(5): e448Ye457. 7. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 2010;362(15):1396Y1406. 8. Strothotte S, Strigl-Pill N, Grunert B, et al. Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial. J Neurol 2010;257(1):91Y97. 9. Cupler EJ, Berger KI, Leshner RT, et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve 2012;45(3):319Y333. 10. Liew WK, Kang PB. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. Ther Adv Neurol Disord 2013;6(3):147Y160.
Continuum (Minneap Minn) 2013;19(6):1698–1702
www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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Genetically Targeted Therapies
11. Murphy SM, Puwanant A, Griggs RC; Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol 2012;72(4):481Y490. 12. Neumann PJ. What we talk about when we talk about health care costs. N Engl J Med 2012;366(7):585Y586. 13. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80(1Y2):148Y158. 14. Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab 2009;96(4):151Y157. 15. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348(3):255Y256. 16. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302(5644):415Y419. 17. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009;326(5954):818Y823. 18. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 2010;467(7313):318Y322. 19. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Vision 1 year after gene therapy for Leber’s congenital amaurosis. N Engl J Med 2009;361(7):725Y727. 20. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012;130(1):9Y24. 21. Pacak CA, Byrne BJ. AAV vectors for cardiac gene transfer: experimental tools and clinical opportunities. Mol Ther 2011;19(9):1582Y1590. 22. Pacak CA, Mah CS, Thattaliyath BD, et al. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006;99(4):e3Ye9. 23. Kornegay JN, Bogan JR, Bogan DJ, et al. Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. Mamm Genome 2012;23(1Y2):85Y108. 24. Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med 2010;363(15):1429Y1437. 25. Lee KJ, Havens PL, Sato TT, et al. Assent for treatment: clinician knowledge, attitudes, and practice. Pediatrics 2006;118(2):723Y730. 26. Martin JB. The pervasive influence of conflicts of interest: a personal perspective. Neurology 2010;74(24):2016Y2021.
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December 2013
![[Bone targeted therapies: new agents].](/assets/img/hold.png)
