CpG oligonucleotides induce an acute murine thrombocytopenia dependent on toll-like receptor 9 and spleen tyrosine kinase pathways.

BACKGROUND: CpG ODN are synthetic single stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers, however, thrombocytopenia is a potential recognized side effect of some sequences. OBJECTIVES: We tested the ability of two CpG ODN (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia. METHODS: BALB/c mice were pre-bled and then injected with titrated doses of CpG ODNs and platelet counts were determined. The mice were treated IVIg or with various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to determine their effects on the thrombocytopenia. RESULTS AND CONCLUSIONS: Compared with saline-treated mice or mice treated with 2'-O-methoxyethyl (MOE)-modified antisense (ASO) ODN, both ODN 2395 and ISIS 120704 induced an acute dose-dependent thrombocytopenia within 3 and 24 hours respectively. The thrombocytopenia was associated with significant increases in plasma monocyte chemoattractant protein 1 (MCP1). Intravenous immunoglobulin (IVIg) administration significantly rescued the CpG ODN-induced thrombocytopenia, as did treatment with either a Syk-inhibitor or TLR9 antagonists. In vitro, CpG ODN could activate human platelets and this correlated significantly with enhanced IVIg- and Syk-dependent phagocytosis by THP-1 monocytes. These results suggest that CpG ODN induce an acute inflammatory-associated (IVIg-sensitive) thrombocytopenia that can be alleviated by Syk- or TLR9-blockade, and an IVIg- and Syk-dependent platelet clearance pathway appears primarily responsible for the thrombocytopenia. Whether these results are applicable to humans still has to be elucidated.

The Role of Subjective Norm in Persuasion Through the Restoration of Personal Freedom.

Human behavior is largely influenced by social norms. While the social norm approach is frequently used in public health campaigns, their effectiveness is inconsistent. This study investigated the role of normative reactance - the amplification of subjective norms as a means of restoring threatened freedom - across two health behaviors: college drinking and STD testing. A 2 (message threat: low vs. high) × 2 (health topic: college drinking vs. STD testing) between-subjects experiment was conducted with 765 participants. The results indicated that, similar to attitudes, subjective norms could also be amplified as a self-justification strategy to restore threatened freedom, which led to reduced intention to follow a message recommendation. In addition, results showed that the role of subjective norms and attitudes can vary across health behaviors and individual differences, particularly concerning an individual's degree of self-monitoring. Theoretical implications, limitations, and future directions are discussed.

A Content Analysis of Online Messages about Sugar-Sweetened Beverages.

Media campaigns can reduce or promote the consumption of sugar-sweetened beverages (SSBs). Brief, US-based English-language online messages were gathered from searchable media platforms, a process that yielded 112 anti-SSB videos and 29 pro-SSB commercials. Using a combination of inductive and deductive methods, a content analysis of those messages was conducted to identify their properties. They were coded for the direction (pro vs. anti), target of the advocacy (e.g., consumption vs. policy), actor demographics (gender, age, and ethnicity), persuasive theme (e.g., excessive sugar, nurturing), and message sensation value. Anti-SSB appeals primarily targeted individual-level consumption behavior. They utilized six persuasive themes and often included more than one theme in a single message. Pro-SSB messages used feel-good themes and utilized only one theme per message. The proportions of adults, adolescents, and children differed by the direction of the advocacy. Black, Hispanic, and Asian actors were under-represented in the anti-SSB sample relative to Whites. Pro-SSB appeals were slightly higher than anti-SSB appeals in message sensation value (p = 0.09). The findings illuminate the message features that characterize the universe of brief anti-SSB appeals available online, highlight messaging disparities, and reveal the absence of certain common, effective persuasive themes.

Toward Multidimensional Message Tailoring to Address COVID-19 and Influenza Vaccine-Hesitancy: A Latent Profile Analysis Approach.

Vaccines remain the best strategy as the COVID-19 pandemic enters into later stages and governments begin to shed pandemic-control measures. Vaccine hesitancy continues to be a major obstacle in efforts to end the pandemic. This study reports formative evaluation research that adopted a multidimensional approach using latent profile analysis to audience segmentation and message targeting. Within the framework of the integrated behavioral model, data were collected from a US national survey to explore the dimensions in which vaccine-confident vs. -hesitant individuals differed significantly across the topics of COVID-19 and influenza. Latent profile analyses were performed to identify subgroups and establish measurement invariance between COVID-19 and influenza vaccines. Matching message strategies were proposed for the distinctive characteristics of the subgroups for both topics and to be tested in future research.

Predicting COVID-19 and Influenza Vaccination Confidence and Uptake in the United States.

This study investigates and compares the predictors of COVID-19 and influenza vaccination confidence and uptake in the U.S. Vaccine hesitancy is defined as the reluctance or refusal (i.e., less than 100% behavioral intention) to vaccinate despite the availability of effective and safe vaccines. Vaccine hesitancy is a major obstacle in the fight against infectious diseases such as COVID-19 and influenza. Predictors of vaccination intention are identified using the reasoned action approach and the integrated behavioral model. Data from two national samples (N = 1131 for COVID-19 and N = 1126 for influenza) were collected from U.S. Qualtrics panels. Tobit regression models were estimated to predict percentage increases in vaccination intention (i.e., confidence) and the probability of vaccination uptake (i.e., intention reaching 100%). The results provided evidence for the reasoned approach and the IBM model and showed that the predictors followed different patterns for COVID-19 and influenza. The implications for intervention strategies and message designs were discussed.

Complement C3d/C4d Deposition on Platelets Correlates with 2'-O-Methoxyethyl Antisense Oligonucleotide-Induced Thrombocytopenia in Monkeys.

2'-O-Methoxyethyl antisense oligonucleotide (2'-MOE ASO)-induced severe thrombocytopenia (TCP) [platelet (PLT) count <50 K/µL] was observed in the Asian-sourced cynomolgus monkeys with low incidence (2%-4% at doses >5 mg/kg/week). The potential mechanisms for TCP were studied using the Mauritian-sourced cynomolgus monkeys, which were shown to be more susceptible to ASO-induced TCP, along with the Asian-sourced animals. ISIS 405879, a 2'-MOE ASO, induced severe TCP (PLT <50 K/µL) in seven of nine Mauritian-sourced monkeys but not in the Asian-sourced monkeys after 16 weeks of treatment at 40 mg/kg/week. Marked increases in PLT-bound C3d/C4d were detected in all thrombocytopenic Mauritian-sourced monkeys but not in the unaffected Mauritian- or Asian-sourced monkeys, suggesting increased PLT clearance due to complement deposition on the PLTs. However, this effect was independent of the ASO-mediated fluid-phase alternative complement activation. A correlation was also observed between serum antiglycoprotein (GP) IIb/IIIa immunoglobulin G (IgG) and PLT reduction. In addition, increases in total serum IgM, anti-PLT IgM, and anti-PLT factor 4 IgM levels were observed in monkeys from both sources but were more evident in the Mauritian-sourced monkeys. These data suggest an enhanced innate immune cell activation to ISIS 405879, leading to increased PLT destruction through complement fixation on the PLTs or PLT crossreacting polyclonal antibody production.

Psychological profiles of COVID vaccine-hesitant individuals and implications for vaccine message design strategies.

COVID-19 has caused tremendous consequences in the U.S., and combating the pandemic requires a significant number of Americans to receive COVID-19 vaccines. Guided by prominent health communication theories, this project took a formative evaluation approach and employed a national sample (N = 1041) in the U.S. to explore the potential differences between vaccine-inclined vs. -hesitant individuals and to generate profiles of hesitant individuals as the foundation for audience segmentation and message targeting. Five distinct profiles emerged in the sample. Characteristics of each profile were described, and appropriate messaging strategies were identified to target each group. Theoretical and practical implications were discussed.

Targeting COVID-19 vaccine-hesitancy in college students: An audience-centered approach.

Objective: The study tested potential factors that differentiated the COVID-19 vaccine-hesitant and -inclined college students and, based on these factors, identified subgroups of the vaccine-hesitant students. Participants: Participants were 1,183 U.S. college students attending four-year universities or community colleges recruited through Qualtrics between January 25 and March 3, 2021. Methods: Participants completed an online survey assessing their COVID-19 vaccination intention, perceived risks of COVID-19 and the COVID-19 vaccines, efficacy beliefs regarding COVID-19 and the COVID-19 vaccines, and emotions toward taking the COVID-19 vaccines. Results: Vaccine-hesitant and -inclined college students varied in their emotions, risk perceptions, and efficacy beliefs regarding the virus and the vaccines. Using these factors as indicators, vaccine-hesitant college students were classified into five latent subgroups with distinct characteristics. Conclusions: In identifying subgroups of the vaccine-hesitant college students, the study has important insights to offer regarding the design of vaccine-promotion messaging strategies targeting the college student population.

Spillover effects of anti-sugar-sweetened beverage messages: From consumption decisions to policy preferences.

BACKGROUND: Intake of sugar-sweetened beverages (SSBs) is associated with many negative health outcomes. Efforts to curb consumption generally take one of two approaches: (a) Individual change based on the communication of personal risk information or (b) policies that limit or disincentivize the behavior, such as restricting access or implementing taxes. METHODS AND RESULTS: Using samples of 2347 persons and 139 pro- and anti-SSB messages, this study tested whether individual-level persuasion attempts would spill over to voting intentions and whether that spillover would amplify or attenuate policy preferences. The influence of anti-SSB messages was seen in (a) direct, positive effects on intention to vote for restrictive policies and in (b) indirect, positive effects where change in intended consumption mediated message impact on change in voting intentions. Anti-SSB messages were generally more powerful than pro-SSB advertising at producing direct and indirect change. Yet, there was evidence of boomerang effects among small numbers of both SSB drinkers and nondrinkers. CONCLUSIONS: Anti-SSB messages that target individual consumption bring about intentions to reduce consumption and increased receptivity to restrictive SSB policies.

Persuasive Messages, Social Norms, and Reactance: A Study of Masking Behavior during a COVID-19 Campus Health Campaign.

Efforts by universities to reduce the spread of COVID-19 include health campaigns intended to encourage students to wear masks. While well-intended, these efforts may produce counter-persuasion (e.g., decrease masking) if they are seen as threatening individuals' freedom to choose. In a rolling cross-sectional study of one university campaign (n = 681), we found that the presence of the campaign did instigate a form of resistance known as reactance and that reactance was negatively associated with masking behavior. Masking was also diminished by the frequency with which respondents observed others not wearing a mask (anti-masking descriptive norm) and the frequency with which respondents observed others expressing disdain for masking (anti-masking injunctive norm). Most of these findings were magnified among students who identified as politically conservative. There was no evidence that the frequency of seeing others speak in favor of masks (pro-masking injunctive norm) produced an increase in masking. The results provide valuable theoretical insights into the causes of reactance and empirical evidence of the risks associated with student-oriented COVID safety campaigns.

Examining and Extending the Influence of Presumed Influence Hypothesis in Social Media.

The influence of presumed influence hypothesis (IPI) is a communication theory accounting for the process of persuasive media effects. The present study integrates theoretical perspectives in persuasion and new and traditional media effects research to investigate the assumptions and explanatory mechanisms of IPI in an experiment. View numbers in social media directly predicted presumed exposure by others and indirectly predicted presumed influence on others, consistent with IPI and inconsistent with the bandwagon heuristic. Presumed exposure predicted presumed influence, consistent with IPI. Other predictors of presumed exposure and presumed influence were also found. Self's evaluation of the message (realism) and engagement in the message (identification) predicted presumed exposure by others and presumed influence on others, supporting the expectation that a motivational mechanism of IPI is self-centric social perception. Social media message view numbers did not predict persuasive outcomes directly, but the evaluation of and engagement in the message did. Finally, the data were inconsistent with the assumption of pervasive mass media reach. This study provides theoretical implications for examining persuasive effects of social media messages, while enhancing and expanding IPI. Limitations of the study and directions for future research are discussed.

Epistemic Egocentrism and Processing of Vaccine Misinformation (Vis-à-vis Scientific Evidence): The Case of Vaccine-Autism Link.

A web-based 2 (preexisting position: vaccine-inclined vs. -hesitant) by 2 (message type: scientific evidence vs. misinformation) experimental study was conducted to investigate individuals' processing of misinformation (vis-à-vis scientific evidence) on the vaccine-autism link within the framework of epistemic egocentrism. Data (N = 996) collected with Qualtrics panel demonstrated that preexisting position shaped individuals' responses to vaccine-related messages differently such that vaccine-hesitant individuals processed the message more superficially while vaccine-inclined individuals more systematically. There was evidence that involvement moderated information processing. Vaccine-hesitant and -inclined individuals' intentions to seek further information and to engage others with opposite views in public deliberation were shaped by message perception and source perceptions (trustworthiness and expertise), but in different patterns. Implications of the findings for vaccine-related health communication are discussed.

Underlying Immune Disorder May Predispose Some Transthyretin Amyloidosis Subjects to Inotersen-Mediated Thrombocytopenia.

Inotersen, a 2'-O-methoxyethyl (2'-MOE) phosphorothioate antisense oligonucleotide, reduced disease progression and improved quality of life in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in the NEURO-TTR and NEURO-TTR open-label extension (OLE) trials. However, 300 mg/week inotersen treatment was associated with platelet count reductions in several patients. Mean platelet counts in patients in the NEURO-TTR-inotersen group remained ≥140 × 109/L in 50% and ≥100 × 109/L in 80% of the subjects. However, grade 4 thrombocytopenia (<25 × 109/L) occurred in three subjects in NEURO-TTR trial, and one of these suffered a fatal intracranial hemorrhage. The two others were treated successfully with corticosteroids and discontinuation of inotersen. Investigations in a subset of subjects in NEURO-TTR (n = 17 placebo; n = 31 inotersen) and OLE (n = 33) trials ruled out direct myelotoxicity, consumptive coagulopathy, and heparin-induced thrombocytopenia. Antiplatelet immunoglobulin G (IgG) antibodies were detected at baseline in 5 of 31 (16%) inotersen-treated subjects in NEURO-TTR, 4 of whom eventually developed grade 1 or 2 thrombocytopenia while on the drug. In addition, 24 subjects in the same group developed treatment-emergent antiplatelet IgG antibodies, of which 2 developed grade 2, and 3 developed grade 4 thrombocytopenia. Antiplatelet IgG antibodies in two of the three grade 4 thrombocytopenia subjects targeted GPIIb/IIIa. Plasma cytokines previously implicated in immune dysregulation, such as interleukin (IL)-23 and a proliferation-inducing ligand (APRIL) were often above the normal range at baseline. Collectively, these findings suggest an underlying immunologic dysregulation predisposing some individuals to immune-mediated thrombocytopenia during inotersen treatment.

Who Will be a Bystander? An Exploratory Study of First-Person Perception Effects on Campus Bystander Behavioral Intentions.

Purpose: The purpose was to explore the underlying mechanisms that drive relationships between knowledge, attitudes and intervening bystander behavior to improve bystander violence prevention program effectiveness. Perceptual effects theory was used to understand third-person and first-person perceptions (TPP and FPP) as related to bystander intervention programs and to what extent perceptual gaps influence one's intention to intervene. Methods: A web-based survey was conducted with 379 undergraduate students recruited from a large, Northeastern University. The survey covered demographics, previous bystander training, self-efficacy to engage in bystander behavior, social desirability of bystander intervention training programs, and perceived effects on self and others. Participants indicated how they would act in six hypothetical dating violence/bullying and sexual violence scenarios, and how they thought an average student on campus would act. Perceived ambiguity and risk for each of the scenarios were also measured. Results: Descriptive statistics, paired-sample t-tests, and multilevel model analyses were conducted. Results showed that a robust first-person perception effect existed (i.e., the student perceived themselves being more influenced by bystander interventions/messages than their peers). The magnitude of FPP was increased by sex (significantly larger gap among female students) and previous training. Conclusions: Results show promise to further tailor and refine bystander interventions and provide directions to improve program effectiveness. Despite study limitations, the results indicate the first-person effect warrants further consideration for programming and messaging. Tailoring bystander training or repeated exposure may increase bystander behaviors. More research is needed to fully uncover TPP/FPP effects, predictors, and impacts on bystander intervention programs.

Mechanisms of Social Media Effects on Attitudes Toward E-Cigarette Use: Motivations, Mediators, and Moderators in a National Survey of Adolescents.

BACKGROUND: Exposure to risk behavior on social media is associated with risk behavior tendencies among adolescents, but research on the mechanisms underlying the effects of social media exposure is sparse. OBJECTIVE: This study aimed to investigate the motivations of social media use and the mediating and moderating mechanisms of their effects on attitude toward electronic cigarette (e-cigarette) use among adolescents. METHODS: Using data from a national sample survey of adolescents (age=14-17 years, N=594), we developed and validated a social media use motivation scale. We examined the roles of motivations in the effect of social media use on risk exposure and risk attitude. RESULTS: Motivations for social media use included agency, self-expression, realism, social learning, social comparison, and filter. These motivations were associated differentially with the frequency of use of Facebook, Instagram, Snapchat, and YouTube. Frequency of social media use was positively associated with exposure to e-cigarette messages across the four platforms (Ps<.001). Exposure to e-cigarette messages on Instagram (P=.005) and Snapchat (P=.03) was positively associated with attitude toward e-cigarette use. Perceived social media realism moderated the effects of e-cigarette message exposure such that when realism was high, the exposure effect was amplified, but when realism was low, the effect was mitigated (P<.001). A three-way interaction effect (P=.02) among exposure, social learning motivation, and social norm on attitude toward e-cigarette use was found. When perceived social norm was high, the moderating effect of social learning motivation on e-cigarette use attitude was amplified, but when social norm was low, the social learning motivation effect was attenuated. CONCLUSIONS: Because perceived social media realism moderates the effect of exposure to e-cigarette messages on attitude toward e-cigarette use, future intervention efforts should address the realism perceptions. The three-way interaction among exposure, social learning motivation, and social norm indicates the importance of addressing both the online and offline social environments of adolescents. The social media use motivation scale, reflecting perceived affordances, is broadly applicable. Understanding social media use motivations is important, as they indirectly influence attitude toward e-cigarette use via frequency of social media use and/or frequency of exposure to e-cigarette messages on social media.

Features of Empathy-Arousing Strategic Messages.

There has been evidence that empathy-arousing messages might be an effective and ethical approach to persuasion in health communication. Knowledge of intrinsic message features is needed to better design and craft such messages. The goals of this research were (a) to identify message features with the potential to arouse state empathy, (b) to verify the association between the identified message features and state empathy, and (c) to determine if state empathy mediates the impact of the message features on persuasion and social stigma. In the present study, a coding scheme was developed for empathy-arousing message features; 532 individuals recruited from Qualtrics Panel each viewed five messages randomly selected from a total of 20 stimuli messages that varied in empathy message features. Multilevel modeling analyses confirmed the association between the identified message features and state empathy; and state empathy's mediating role of message feature effects on persuasion and social stigma.

Chronic Toxicity Assessment of 2'-O-Methoxyethyl Antisense Oligonucleotides in Mice.

Advances in antisense oligonucleotide (ASO) chemistry and screening have enabled the design and selection of molecules that are optimized for a particular therapeutic application in terms of both potency and tolerability. The most-well studied of the chemically modified ASOs are single-stranded antisense inhibitors with phosphorothioate backbones and 2'-O-methoxyethyl modifications (2'-MOE ASO). The 2'-MOE chemical modification in the design of the ASO has conferred increased hybridization affinity, increased stability, and/or enhanced tissue residence time, resulting in better potency and pharmacokinetics. Compound screening and selection are also important in optimizing the tolerability of intended therapeutic antisense inhibitors. In this study, we report the chronic toxicity of multiple 2'-MOE ASOs in mice for several representative compounds that have progressed to later phases of clinical development. The results show that these 2'-MOE ASOs selected for development have consistent behavior between sequences, have tolerability profiles suitable for chronic administration, and exhibit a relative lack of progression of findings observed in subchronic studies in mice.

Investigation into the Mechanism(s) That Leads to Platelet Decreases in Cynomolgus Monkeys During Administration of ISIS 104838, a 2'-MOE-Modified Antisense Oligonucleotide.

ISIS 104838, a 2'-O-methoxyethyl (2'-MOE)-modified antisense oligonucleotide (ASO), causes a moderate, reproducible, dose-dependent, but selflimiting decrease in platelet (PLT) counts in monkeys and humans. To determine the etiology of PLT decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of ISIS 104838 (30-60 mg/kg/week). Monkeys were also injected intravenously with 111Indium(In)-oxine-labeled PLTs to investigate PLT sequestration. In response to continued dosing, PLT counts were decreased by 50%-90% by day 30 in all monkeys. PLT decreases were accompanied by 2- to 4.5-fold increases in immunoglobulin M(IgM), which were typified by a 2- to 5-fold increase in antiplatelet factor 4 (antiPF4) IgM and antiPLT IgM, respectively. Monocyte chemotactic protein 1 increased upon dosing of ISIS 104838, concomitant with a 2- to 6-fold increase in monocyte-derived extracellular vesicles (EVs), indicating monocyte activation but not PLT activation. Despite a 2- to 3-fold increase in von Willebrand factor antigen in all monkeys following ASO administration, only 2 monkeys showed a 2- to 4-fold increase in endothelial EVs. Additionally, a ∼60 - 80%% increase in PLT sequestration in liver and spleen was also observed. Collectively, these results suggest the overall increase in total IgM, antiPLT IgM and/or antiPF4 IgM, in concert with monocyte activation contributed to increased PLT sequestration in spleen and liver, leading to decreased PLTs in peripheral blood.

Reduction in ocular complement factor B protein in mice and monkeys by systemic administration of factor B antisense oligonucleotide.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries, and the complement system plays an important role in the pathogenesis of AMD. Inhibition of complement factor B, a key regulator of the alternative pathway, is implicated as a potential therapeutic intervention for AMD. Here we investigated the effect of liver factor B reduction on systemic and ocular factor B levels. METHODS: Second-generation antisense oligonucleotides (ASOs) targeting mouse and monkey factor B mRNA were administered by subcutaneous injection to healthy mice or monkeys, and the level of factor B mRNA was assessed in the liver and the eye. In addition, the factor B protein level was determined in plasma and whole eyes from the treated animals. RESULTS: Mice and monkeys treated with factor B ASOs demonstrated a robust reduction in liver factor B mRNA levels with no change in ocular factor B mRNA levels. Plasma factor B protein levels were significantly reduced in mice and monkeys treated with factor B ASOs, leading to a dramatic reduction in ocular factor B protein, below the assay detection levels. CONCLUSIONS: The results add to the increasing evidence that the liver is the main source of plasma and ocular factor B protein, and demonstrate that reduction of liver factor B mRNA by an ASO results in a significant reduction in plasma and ocular factor B protein levels. The results suggest that inhibition of liver factor B mRNA by factor B ASOs would reduce systemic alternative complement pathway activation and has potential to be used as a novel therapy for AMD.

Assessment of the Effects of 2'-Methoxyethyl Antisense Oligonucleotides on Platelet Count in Cynomolgus Nonhuman Primates.

Decreases in platelet (PLT) counts observed in nonhuman primates (NHPs) given 2'-O-methoxyethyl modified antisense inhibitors (2'-MOE ASOs) have been reported, but the incidence and severity of the change vary considerably between sequences, studies, and animals. This article will broadly illustrate the spectrum of effects on PLT count in NHPs. From queries of an NHP safety database representing over 102 independent 2'-MOE ASOs, from 61 studies and >2200 NHPs, two patterns of PLT changes emerged. The first is a consistent and reproducible decrease in group mean values, observed with about 30% of the compounds, in which PLT count typically remains ≥150K cells/µL. The second is a sporadic decrease in PLTs to <50K cells/µL (2%-4% incidence at doses >5 mg/kg) that is often not reproducible. In both cases, the reduction in PLT count is dose dependent and reversible. The human relevance of PLT change observed in NHPs was investigated using ISIS 404173. In a chronic NHP study (20 mg/kg/wk for 26 weeks), a gradual decrease in group mean PLT count was observed at ≥10 mg/kg/wk, which plateaued by 13 weeks generally within the normal range and was maintained through 26 weeks of treatment. However, PLT counts <50K cells/µL occurred in 1 of 16 NHP at 10 mg/kg/wk and 3 of 16 NHP at 20 mg/kg/wk. In a 26-week double-blind, placebo-controlled Phase 2 trial, 62 patients were treated with 200 mg/wk ISIS 404173 (∼3.3 mg/kg/wk) there was an increased incidence of PLT count >30% decreased compared to baseline but no incidence of PLT <75K cells/µL. Based on these data, the consistent, self-limiting PLT reduction seen in NHP may translate to humans, but these changes appear to be of limited clinical significance. However, NHPs appear to overpredict the incidence of sporadic PLT <50K cells/µL compared to humans.