Charles Jennette

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

BackgroundFabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day.MethodsTwo open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology.ResultsCompared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.ConclusionsMigalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.Trial registrationClinicaltrial.gov: NCT00283959 and NCT00283933

Antineutrophil cytoplasmic antibodies directed against bactericidal/permeability-increasing protein detected in children with cystic fibrosis inhibit neutrophil-mediated killing of Pseudomonas aeruginosa.

Antineutrophil cytoplasmic antibodies (ANCA) directed against bactericidal/permeability-increasing protein (BPI) were repeatedly found in cystic fibrosis (CF) patients. We analyzed the effect of BPI-ANCA in inhibiting neutrophil-mediated killing of Pseudomonas aeruginosa. The bactericidal effect expressed as percentage of killed bacteria after 1 h incubation with neutrophils was 55% when the neutrophils were pretreated with normal human serum, ranged from 49 to 63% with the sera from control BPI-ANCA-negative groups and sharply decreased to the mean 30.5% (range 8-51%) in the presence of BPI-ANCA. Furthermore, the effect mediated by BPI-ANCA was dose dependent and reflected the titer of BPI-ANCA in tested sera.

Malignant pulmonary lymphoproliferative angiitis. A monoclonal neoplasm

A 55‐year‐old female developed a rapidly fatal, infiltrative, bilateral pulmonary disease. Open lung biopsy and subsequent autopsy revealed diffuse involvement by a malignant lymphoproliferative condition showing a striking angiocentric and angioinvasive pattern. This feature, together with microscopic involvement of hilar lymph nodes, bone marrow, spleen, and other viscera suggested lymphomatous transformation of lymphomatoid granulomatosis (LYG). The paucity of necrosis and of the typical polymorphic infiltrate was at variance with the classical description of that condition; however, the bilaterality of the process and the distinctive angioinvasive growth pattern were unlike the typical primary pulmonary lymphoma. Plasmacytoid cells were observed both by light and electron microscopy. Immunohistochemical evaluation characterized this disease as a monoclonal lymphoproliferative malignancy.