J. David Ingram

Bio: J. David Ingram is an academic researcher from Boston Children's Hospital. The author has contributed to research in topics: Pancreatitis & Acute pancreatitis. The author has an hindex of 5, co-authored 7 publications receiving 1651 citations. Previous affiliations of J. David Ingram include University of Colorado Denver & Anschutz Medical Campus.

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.

Abstract: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597.)

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia.

Abstract: 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.

Successful management with octreotide of a child with L-asparaginase induced hemorrhagic pancreatitis

Abstract: Background. Octreotide is a synthetic somatostatin analogue which has been suggested for use in the management of acute pancreatitis. While studies have looked at octreotide use in the setting of pancreatitis due to chronic alcohol use or trauma, little is known of its role in management of drug induced acute pancreatitis, particularly in the pediatric setting. Patients and Methods. We present a case of a 51/2-year-old white female who developed severe, necrotizing, hemorrhagic pancreatitis with pseudocyst formation secondary to L-asparaginase use as a part of her therapy for acute lymphoblastic leukemia (ALL). She was managed initially with intravenous fluids, bowel rest, nasogastric suctioning, parenteral narcotices, and broad spectrum antibiotics. In-addition, within 12 hours of admission to The Children's Hospital (TCH) in Denver, Colorado, she began therapy with octreotide (5 micrograms/kg/day IV divided b.i.d.). With this management, her pseudocyst decompressed without need for surgical intervention, her pancreatitis fully resolved, and she recovered full pancreatic function without any long-term sequelae. Conclusion. Use of octreotide may have served a role in limiting the severity of the disease process in this case. Further studies need to be done to verify its usefulness in this setting.

Molecular Genetic Analysis of a Small Bowel Primitive Neuroectodermal Tumor

Abstract: We present a pediatric peripheral primitive neuroectodermal tumor (pPNET) localized exclusively to the small bowel. The tumor presented in an adolescent male and the diagnosis was confirmed by electron microscopy, CD99 immunopositivity, and molecular genetic analysis that demonstrated an EWS-FLI1 type 2 fusion transcript. This case report and a review of the literature underscore the considerable phenotypic overlap in EWS-related tumors in this site and the necessity for molecular genetic analysis to permit accurate classification.

Guidelines for the management of hemophilia.

Abstract: Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges

Abstract: In vivo gene replacement for the treatment of inherited disease is one of the most compelling concepts in modern medicine. Adeno-associated virus (AAV) vectors have been extensively used for this purpose and have shown therapeutic efficacy in a range of animal models. Successful translation to the clinic was initially slow, but long-term expression of donated genes at therapeutic levels has now been achieved in patients with inherited retinal disorders and haemophilia B. Recent exciting results have raised hopes for the treatment of many other diseases. As we discuss here, the prospects and challenges for AAV gene therapy are to a large extent dependent on the target tissue and the specific disease.

WFH Guidelines for the Management of Hemophilia, 3rd edition

Abstract: Alok Srivastava 1 | Elena Santagostino 2 | Alison Dougall 3 | Steve Kitchen 4 | Megan Sutherland 5 | Steven W. Pipe 6 | Manuel Carcao 7 | Johnny Mahlangu 8 | Margaret V. Ragni 9 | Jerzy Windyga 10 | Adolfo Llinás 11 | Nicholas J. Goddard 12 | Richa Mohan 13 | Pradeep M. Poonnoose 14 | Brian M. Feldman 15 | Sandra Zelman Lewis 16 | H. Marijke van den Berg 17 | Glenn F. Pierce 18 | on behalf of the WFH Guidelines for the Management of Hemophilia panelists and co-authors*

Emerging Issues in AAV-Mediated In Vivo Gene Therapy

Abstract: In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others. Clinical translation of novel and effective "therapeutic products" is, however, a long process that involves several cycles of iterations from bench to bedside that are required to address issues encountered during drug development. For the AAV vector gene transfer technology, several hurdles have emerged in both preclinical studies and clinical trials; addressing these issues will allow in the future to expand the scope of AAV gene transfer as a therapeutic modality for a variety of human diseases. In this review, we will give an overview on the biology of AAV vector, discuss the design of AAV-based gene therapy strategies for in vivo applications, and present key achievements and emerging issues in the field. We will use the liver as a model target tissue for gene transfer based on the large amount of data available from preclinical and clinical studies.