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IntroductionThe Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM.MethodsMILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV1; 51–70%versus≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum.ResultsIn the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±seFEV1slope −17±3versus−3±3 mL·month−1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (−17±3versus−1±2 mL·month−1; p<0.0001) and post-menopausal patients (−3±3versus6±3 mL·month−1; p=0.04) exhibited a beneficial response in mean±seFEV1slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL−1identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus.ConclusionsIn LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.

Aims/hypothesis Human α1-antitrypsin (hAAT) gene therapy prevents type 1 diabetes in a NOD mouse model of diabetes. However, repeated i.p. injections of hAAT into NOD mice leads to fatal anaphylaxis. The aim of the study was to determine if an alternative route of administration avoids anaphylaxis and allows evaluation of hAAT's potential for diabetes prevention and reversal. We also sought to determine if the addition of granulocyte colonystimulating factor (G-CSF), augments hAAT's capacity to prevent or reverse disease in the NOD mice. Methods To evaluate hAAT pharmacokinetics, serum hAAT levels were monitored in NOD mice receiving a single dose (2 mg) of hAAT by i.p., s.c. or i.d. injection.

SummaryPrevious studies have shown that human alpha-1 antitrypsin (hAAT) gene delivery prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Furthermore, hAAT protein administration prolongs acceptance of islet allografts. Therefore, we evaluated the use of purified hAAT protein therapy to prevent T1D in NOD mice. Female NOD, non-obese resistant (NOR), Balb/c and C57BL/6 mice were injected intraperitoneally with vehicle alone or vehicle containing hAAT, human albumin or mouse albumin (or mg/injection/mouse; 2¥/week). Preparations of clinical-grade hAAT included API®, Aralast®, Prolastin® and Zemaira®. Surprisingly, hAAT administration was associated with a high rate of fatal anaphylaxis. In studies seeking T1D prevention at 4 weeks of age, 100% mice died after six injections of hAAT. When administrated at 8-10 weeks of age, most (80-100%) NOD mice died following the fourth injection of hAAT, while 0% of Balb/c and C57BL/6 mice and 10% of NOR mice died. Interestingly, repeated injections of human albumin, but not mouse albumin, also induced sudden death in NOD mice. Antibodies to hAAT were induced 2-3 weeks after hAAT administration and death was prevented by treatment with anti-platelet-activating factor along with anti-histamine. In studies of disease reversal in NOD mice, using the four pharmaceutical grade formulations of hAAT, anaphylactic deaths were observed with all hAAT preparations. The propensity for fatal anaphylaxis following antigenic administration appears to be NOD-but not hAATspecific. The susceptibility of NOD mice to hypersensitivity provides a significant limitation for testing of hAAT. Development of strategies to avoid this unwanted response is required to use this promising therapeutic agent for T1D.

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