Browsing by Author "Donna DiMichele"

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    Ethical issues in haemophilia
    (2006-07-01) Donna DiMichele; A. Chuansumrit; A. J. London; A. R. Thompson; C. G. Cooper; R. M. Killian; L. F. Ross; D. Lillicrap; J. Kimmelman; Weill Cornell Medical College; Mahidol University; Carnegie Mellon University; Puget Sound Blood Center; University of Chicago; Queen's University, Kingston; McGill University; New York-Presbyterian/Weill Cornell
    Ethical issues surrounding both the lack of global access to care as well as the implementation of advancing technologies, continue to challenge the international haemophilia community. Haemophilia is not given the priority it deserves in most developing countries. Given the heavy burdens of sickness and disease and severe resource constraints, it may not be possible to provide effective treatment to all who suffer from the various 'orphan' diseases. Nevertheless, through joint efforts, some package of effective interventions can be deployed for a significant number of those who are afflicted with 'orphan' diseases. With cost-effective utilization of limited resources, a national standard of care is possible and affordable. Gene-based diagnosis carries attendant ethical concerns whether for clinical testing or for research purposes, even as the list of its potential benefits to the haemophilia community grows rapidly. As large-scale genetic sequencing becomes quicker and cheaper, moving from the research to the clinic, we will face decisions about the implementation of prenatal, neonatal and other screening programs. Such debates will require input from not just the health care professionals but from all stakeholders in the haemophilia community. Finally, long-term therapeutic success gene transfer in small and large animal models raises the question of when and in which patient population the novel therapeutic approach should first be studied in humans with haemophilia. Although gene therapy represents a worthy goal, the central question for the haemophilia community should be whether it wishes to volunteer itself as a model for a much broader set of innovations. © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd.
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    Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia
    (2012-03-01) C. Li; N. Narkbunnam; R. J. Samulski; A. Asokan; G. Hu; L. J. Jacobson; M. J. Manco-Johnson; P. E. Monahan; Marilyn J. Manco-Johnson; Brenda Riske; Ray Kilcoyne; Michael L. Manco-Johnson; Sharon Funk; Linda Jacobson; J. David Ingram; Thomas C. Abshire; Amy D. Shapiro; Michele R. Hacker; Leonard A. Valentino; W. Keith Hoots; Deborah Brown; George R. Buchanan; Donna DiMichele; Michael Recht; Cindy Leissinger; Shirley Bleak; Alan Cohen; Prasad Mathew; Alison Matsunaga; Desiree Medeiros; Diane Nugent; Gregory A. Thomas; Alexis A. Thompson; Kevin McRedmond; J. Michael Soucie; Harlan Austin; Bruce L. Evatt; The University of North Carolina at Chapel Hill; Mahidol University; University of Colorado School of Medicine; University of Colorado Health Sciences Center; Emory University; Blood Center of Milwaukee; Indiana Hemophilia and Thrombosis Center; Harvard Medical School; Rush University Medical Center; University of Texas System; University of Southwestern Medical Center; Weill Cornell Medical College; Phoenix Children's Hospital; Tulane University; Primary Children's Medical Center; University of Pennsylvania; University of New Mexico; UCSF Benioff Children's Hospital Oakland; University of Hawaii at Manoa; CHOC Children`s UC Irvine School of Medicine; Oregon Health and Science University; Northwestern University; Palmetto Health Richland; Centers for Disease Control and Prevention
    Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs. © 2012 Macmillan Publishers Limited All rights reserved.