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BACKGROUND Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.

Publisher Summary This chapter discusses the effects of brain-derived neurotrophic factor (BDNF) on injured dopaminergic neurons. The degeneration of dopaminergic neurons of the substantia nigra is characteristic for Parkinson's disease and the loss of dopaminergic function is most likely responsible for the majority of behavioral deficits of the disease. The identification of a trophic factor able to promote survival and function of dopaminergic neurons and to protect them from degeneration after injury could have significant impact on the future treatment of Parkinson's disease. BDNF, a growth factor belonging to the neurotrophin protein family, which includes nerve growth factor (NGF), stimulates developmental growth and differentiation of dopaminergic neurons in culture. The pretreatment of cultured dopaminergic neurons with BDNF diminishes the susceptibility of these cells to intermediate concentrations of the selective dopaminergic neurotoxin MPP+. In contrast to these actions in vitro, it is found that intraventricular BDNF administration is unable to protect axotomized dopaminergic neurons from degeneration in a similar way as NGF offers protection for axotomized cholinergic neurons. However, these findings do not generally exclude that adult dopaminergic neurons are responsive to BDNF.

Publisher Summary Neurotrophic factors are found among several protein families, including neurotrophins, fibroblast growth factors, epidermal growth factor protein family, lymphokines, and others. The nerve growth factor (NGF) represents the initially discovered member of the protein family called neurotrophins, whose other known members are brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and neurotrophin-5 (NT-5). All known neurotrophins are synthesized as large precursor proteins from which an active protein of approximately 120 amino acids is cleaved at the N-terminal. In this chapter, the studies demonstrate that NGF is more effective than BDNF in protecting cholinergic septo-hippocampal neurons from degenerative changes induced by lesions in adult rat brains. BDNF treatment provides partial protection of cholinergic cell bodies in the septal area but fail to enhance presynaptic cholinergic function in the partially deafferentated hippocampus. In contrast, NGF treatment protects the entire population of cholinergic cell bodies and significantly elevated several measures of hippocampal cholinergic function. These findings indicate that NGF remains the agent of choice, when attempting to protect forebrain cholinergic neurons from degeneration induced by injury or disease.

Publisher Summary In an attempt to clarify the degree of selectivity of the actions of various neurotrophic substances, this chapter uses previously established cell culture models of fetal rat septum, pons, and ventral mesencephalon. Septal cholinergic cells in culture respond to nerve growth factor (NGF) in various ways, among them by increasing the activity of the enzyme choline acetyltransferase. Pontine cholinergic neurons, located in the pedunculopontine and dorsolateral tegmental nuclei, share some of the morphological characteristics of basal forebrain cholinergic neurons and have medium- to large-sized cell bodies and long centrally ascending axons. However, this cell group has been shown in vitro not to respond to NGF. Cultures of the ventral mesencephalon were used to test for effects of trophic factors on dopaminergic cells of the substantia nigra. Trophic actions on septal and pontine cholinergic neurons and mesencephalic dopaminergic neurons have been examined in the chapter for basic fibroblast growth factor, insulin, insulin-like growth factors-I (IGF-I), IGF-II, epidermal growth factor, and NGF.