Catherine E. McGuinn

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Background The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. Methods We infused a single‐stranded adeno‐associated viral (AAV) vector consisting of a bioengineered capsid, liver‐specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. Results No serious adverse events occurred during or after vector infusion. Vector‐derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady‐state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow‐up of 492 weeks among all the participants (range of follow‐up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver‐enzyme levels developed in 2 participants and resolved with short‐term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. Conclusions We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene‐derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092.)

Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.

PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation‐specific PCR in 215 cases of various subsets of myeloid‐ and lymphoid‐lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B‐cell (81.9%) and T‐cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation‐mediated inactivation of PCDH10 were less sensitive to commonly used leukemia‐specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid‐lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.

Pilot Trial of Risk-Adapted Cyclophosphamide Intensity Based Conditioning and HLA Matched Sibling and Unrelated Cord Blood Stem Cell Transplantation in Newly Diagnosed Pediatric and Adolescent Recipients with Acquired Severe Aplastic Anemia

Cyclophosphamide‐based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non‐malignant diseases.

Fetal and Neonatal Alloimmune Thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia is characterized by the presence of transient isolated thrombocytopenia secondary to maternal antibodies against paternally inherited antigens expressed on the fetal platelet. Fetal and neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia ( in utero and perinatal intracranial hemorrhage with resulting long term neurological disability or death. Prompt investigation of thrombocytopenia is critical for management of the neonate and future pregnancies. Significant improvement in fetal/neonatal outcome has occurred with maternal treatment with intravenous immune globulin.

Radionuclide synovectomy/synoviorthesis (RS) in patients with bleeding disorders: A review of patient and procedure demographics and functional outcomes in the ATHNdataset

Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited.

Acquired Neonatal Thrombocytopenia

This chapter will focus on the acquired etiologies of neonatal thrombocytopenia. Neonatal thrombocytopenia occurs in 1–2% of healthy term neonates, but is more common in the neonatal intensive care unit (NICU) where thrombocytopenia occurs in up to one third of all admissions. Thrombocytopenia in the fetus and neonate is defined as platelet count <150,000/μl while acknowledging this reference range is not well-standardized for preterm infants, and that mild thrombocytopenia may overlap with normal values. Thrombocytopenic neonates may present symptomatically with petechiae, hematomas and gastrointestinal, umbilical or intracranial bleeding. The increased risk of life-threatening bleeding that accompanies severe thrombocytopenia and prematurity makes the accurate diagnosis and intervention of acquired thrombocytopenia critical.