Joseph L. Witztum

Abnormal Iron Deposition Associated With Lipid Peroxidation in Transgenic Mice Expressing Interleukin-6 in the Brain

Transgenic mice, named GFAP-IL6, that express intcrlcukin-6 in astrocytes in the central nervous system (CNS) have a constitutive blood-brain barrier (BBB) defect and develop a progressive neurodegenerative disease. Based on ultrastructural observations showing electron-dense pigment in the brain of the GFAP-IL6 mice, we hypothesized that iron metabolism was altered in the brains of these animals. Enhanced histochemical methods revealed abnormal iron deposition in the cerebellum from 1 month of age that worsened with progression of the disease. Immunohistochemical analysis of ironbinding proteins (IBP) showed increased ferritin immunoreactivity and a decreased signal from the transferrin receptor in symptomatic animals. Atomic absorption spectroscopy revealed a 40% increase of total iron concentration in the cerebellum at the symptomatic stage. In order to obtain evidence that accumulation of this oxidizing metal was toxic, we looked for the presence of oxidative damage. Using the MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the neocortex and the cerebellum in symptomatic animals. Ultrastructural analysis indicated lipofuscin deposition at the sites of neuro-axonal degeneration and abnormal iron deposition. These results suggest that the IL6-induced BBB defect precipitates iron accumulation in the GFAP-IL6 mouse brain and that subsequent IBP regulation mediates protective responses. As these defenses become overwhelmed, the iron overload seems to promote LP, which may contribute to the neurodegeneration that ensues. This transgenic mouse model of IL6-mediated neurodegeneration provides a unique opportunity to examine several aspects of iron metabolism in the brain, including its entry at the site of the BBB, its distribution through the IBP, and its mechanisms of toxicity.

POTENT ANTISENSE OLIGONUCLEOTIDES TO APO(A) NORMALIZE PLASMA LP(A) LEVELS IN THE MAJORITY OF PEOPLE WITH ELEVATED LP(A): RESULTS OF ISIS-APO(A)RX PHASE 2 AND ISIS-APO(A)-LRX PHASE 1 TRIALS

Elevated Lp(a) levels are causal, independent predictors of CVD and aortic stenosis (AS). Specific therapies to potently lower Lp(a) are lacking. We assessed the safety and efficacy of ISIS-APO(a)Rx in patients with elevated Lp(a) and of ISIS-APO(a)-LRx, an optimized antisense oligonucleotide (ASO)