Faculty Bibliography

Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 x 10(11) vector genomes (vg)/kg to 1.8 x 10(12) vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals

The goal of gene therapy for bleeding disorders is to provide stable insertion and expression of a particular gene whose absence is responsible for a particular disease. The bleeding disorders for which the most basic and clinical research has been completed are the hemophilias factor VIII deficiency and factor IX deficiency. These X-linked diseases are caused by single-gene mutations; replacement of the defective gene has not only resulted in clinical and biochemical improvement in animal models but also provided promising results in phase I clinical trials. An ideal gene transfer approach to the treatment of hemophilia would require a minimally invasive procedure for gene delivery, have minimal associated morbidity, and result in long-term transgene expression, ideally yielding factor levels in the therapeutic range. Multiple approaches to gene transfer in the hemophilias are currently under investigation

Two boys with severe factor VIII deficiency that initially presented with acute onset of joint pain and swelling consistent with an uncomplicated hemarthrosis are reported. When appropriate management failed to provide resolution of symptoms, alternate diagnoses were considered. Both boys ultimately had complex regional pain syndrome (CRPS) diagnosed. The delay in diagnosis contributed to prolonged patient discomfort and lack of appropriate therapy. Complex regional pain syndrome encompasses a group of disorders that are characterized by pain severity or duration disproportionate to that expected. It is uncommon in the pediatric population. Because early diagnosis and appropriate treatment may improve outcome, it is important for practitioners to consider CRPS in the differential diagnosis of persistent pain in children with hemophilia

A female, term newborn born to a mother with a history of idiopathic thrombocytopenic purpura and antinuclear antibodies, single-stranded A antibody, and IgM anticardiolipin antibodies presented with immune thrombocytopenia, disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemia, and a characteristic lupus rash in the periorbital areas. She responded to combined treatment with dexamethasone and intravenous immunoglobulin (IVIG). At age 9 months, she was readmitted with severe thrombocytopenia, DIC, and microangiopathic hemolytic anemia. She again responded to IVIG. This suggests that microangiopathic hemolysis can be a presenting symptom in neonatal lupus erythematosus and that reoccurrence of the microangiopathic hemolysis may occur even after the disappearance of lupus antibodies