The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

Background In psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell-derived cytokines. Evidence suggests that the Th17 cell cytokine interleukin-17 (IL-17) may play a role in disease pathogenesis. Objective To understand the impact that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods We examined skin lesions obtained from 40 subjects participating in a phase 1, randomized, double-blind, placebo-controlled trial of an anti-IL-17 monoclonal antibody, ixekizumab (previously LY2439821), in which subjects received subcutaneous 5mg, 15mg, 50mg or 150mg ixekizumab or placebo at weeks 0, 2, and 4. Results There were significant, dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative reverse transcriptase polymerase chain reaction and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and Tumor necrosis factor (TNF) was of higher magnitude at 2 weeks than in prior studies with TNF antagonism. Conclusion Our data suggest that IL-17 is a key “driver” cytokine in psoriasis that activates pathogenic inflammation. Neutralizing IL-17 with ixekizumab may be a successful therapeutic strategy.

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Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.

Objectives To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identified potential endpoints for future treatment trials. Study design Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric MRI, respectively. Liver and spleen volumes, CSF and urine biomarker levels were measured. Results Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing form of MPS IIIA (RP), and 5, a more slowly progressing form (SP). Children with RP plateaued in development by 30 months, followed by rapid regression after 40 to 50 months. Cognitive developmental quotients (DQ) in patients with RP showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with SP had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and CSF and urine HS levels were elevated and relatively constant over time. Conclusions DQ and cortical gray matter volumes are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy.