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Biomedical subjects

Paul E Monahan

Publications and source records attributed to Paul E Monahan.

9 recordsLinked to original sources
PubMed2011

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector.

Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer.

Amino Acid Sequence↗
PubMed2005

A classification system for cross-reactive material-negative factor XI deficiency.

The bleeding disorder associated with factor XI (fXI) deficiency is typically inherited as an autosomal recessive trait. However, some fXI mutations may be associated with dominant disease transmission. FXI is a homodimer, a feature that could allow certain mutations to exert a dominant-negative effect on wild-type fXI secretion through heterodimer formation. We describe 2 novel fXI mutations (Ser225Phe and Cys398Tyr) that form intracellular dimers, are secreted poorly, and exhibit dominant-negative effects on wild-type fXI secretion in cotransfection experiments. Available data now suggest that mutations associated with crossreactive material-negative fXI deficiency fall into 1 of 3 mechanistic categories: (1) mutations that reduce or prevent polypeptide synthesis, (2) polypeptides that fail to form intracellular dimers and are retained in cells as monomers, and (3) polypeptides that form dimers that are not secreted. The latter category likely accounts for many cases of dominant disease transmission.

Adult↗
PubMed2004

Creation of a mouse expressing defective human factor IX.

The majority of cases of human hemophilia B are the result of missense mutations in the coagulation factor IX gene and defective circulating factor IX is detectable in most patients. The available mouse factor IX knockout models of hemophilia B (FIXKO mouse) reproduce the bleeding phenotype of human hemophilia B, but because the models produce no factor IX they fail to reproduce the dominant human phenotype. We have created a human factor IX mouse model of hemophilia B (R333Q-hFIX mouse) by homologous recombination in embryonic stem cells. The mouse expresses no mouse factor IX, but instead expresses a missense mutant human factor IX from the mouse FIX promoter. Mutant human factor IX mRNA transcript and circulating human factor IX are detectable throughout development, but factor IX activity is less than 1% and the mouse exhibits the hemophilic phenotype. When R333Q-hFIX mice were challenged by intramuscular injection of adeno-associated virus expressing human factor IX, factor IX expression without the development of antibodies was observed. In contrast, given the same treatment, FIXKO mice consistently develop antibodies. Our R333Q-hFIX mice strain will complement the FIXKO mice for studying factor IX circulating kinetics and gene therapy.

Alanine↗
PubMed2004

Factors affecting choice of hemostatic agent for the hemophilia patient with an inhibitor antibody.

Achieving adequate hemostasis in patients with hemophilia and high-titer inhibitor antibodies remains a challenge despite the development of plasma-derived and recombinant therapies to bypass the inhibitory effect. A group of hemophilia treaters met to examine the factors that influence physician choices among the very costly and cumbersome available therapies. Specific knowledge deficits in need of prospective research were identified with respect to the rational treatment of inhibitor patients.

Antibodies↗
PubMed2002

Hemophilia gene therapy: update.

Gene transfer is an exciting and potentially important treatment approach for hemophilia A and B. Four phase I clinical trials of the safety of gene transfer in hemophilia A or B have been completed and two more trials are currently underway. The results of these trials indicate that gene transfer in hemophilia with the vectors and doses used is safe and well tolerated. Efforts continue to understand the basic biology and improve the efficiency of gene transfer.

Animals↗
PubMed2002

Safety of adeno-associated virus gene therapy vectors: a current evaluation.

An increasing number of strategies for molecular treatment of disease rely on the adeno-associated virus (AAV) as a therapeutic gene delivery vector. One of the most attractive features of this viral DNA vector is the perceived safety of AAV gene delivery. Recent applications in human clinical trials support the safety record established in preclinical trials, with evidence of gene transfer in the absence of cellular immune responses or tissue disturbance. Nevertheless, many aspects of the biology of the wild type AAV and its derivatives are still being explored. While the therapeutic potential of novel recombinant AAV therapeutics appears promising, recent insights suggest aspects of their pharmacokinetics, biodistribution and toxicity that require consideration to achieve the safest application of these molecular medicines.

Animals↗
PubMed2002

Thrombosis in children: current perspective and distinct challenges.

Coincident with a true increase in the incidence of thrombosis in childhood has come an appreciation of the impact of thromboembolic events upon children. In part, the greater awareness of childhood thrombosis reflects improved diagnostic imaging, which allows more sensitive identification of clots in infants and children. At the same time, advances in supportive care have meant that more children are being exposed to, surviving and living with thromboembolic risk factors and complications than previously. Because data regarding pediatric thrombosis have been lacking, treatment strategies have been extrapolated from experience in adults. This approach, however, results in diagnostic and therapeutic pitfalls. An understanding of issues unique to pediatric thrombosis is required; recent insights and the ongoing challenges are reviewed.

Adolescent↗
PubMedDate not supplied

Interval laparoscopic appendectomy for appendicitis complicated by pylephlebitis.

BACKGROUND: Although rare, portal mesenteric venous thrombosis and pylephlebitis remain potential life-threatening sequelae of ruptured appendicitis in children. Treatment recommendations from recent reports have included urgent exploratory laparotomy with appendectomy, prolonged intravenous antibiotic therapy, and anticoagulation for up to a year. METHODS: This report describes successful management of pylephlebitis and mesenteric venous thrombosis complicating ruptured appendicitis with intravenous antibiotics and anticoagulation followed by interval laparoscopic appendectomy. RESULTS: A previously healthy 5-year-old girl was diagnosed with ruptured appendicitis complicated by pylephlebitis and mesenteric venous thrombosis at the time of presentation. She was treated with intravenous antibiotics and anticoagulated for 3 months. She subsequently underwent interval laparoscopic appendectomy. At 3-year follow-up, she is healthy without evidence of adverse sequelae. DISCUSSION: This is the first reported case of successful, minimally invasive management of ruptured appendicitis complicated by mesenteric venous thrombosis and pylephlebitis. CONCLUSION: Similar treatment of other children with this rare presentation seems reasonable.

Anti-Bacterial Agents↗