Naslov
Pharmacological Changes Induced by Administration of PEGylated IFNbeta-1a in Healthy Volunteers

Autori
Miller, Larisa ; Lerner, Michaela ; Crossman, Mary ; Hitchman, Stacy ; Davar, Gudarz ; Subramanyam, Meena

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Skup
American Academy of Neurology Annual Meeting

Mjesto i datum
Toronto, Kanada, 10.04.2010. - 17.04.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Pharmacology; biomarker; PEGylated interferon-beta

Sažetak
Background: PEGylated interferon beta-1a (PEG-IFN beta-1a) is being developed to address the significant unmet need for safe, effective, and convenient therapies for patients with relapsing multiple sclerosis (RMS). The phase 3 ADVANCE study is currently enrolling RMS patients with the goal of evaluating the safety and efficacy of PEG-IFN beta-1a (125 μg) administered once every 2 or 4 weeks. An increase in IL-10 mRNA levels and decrease in IL-23 mRNA levels in peripheral blood mononuclear cells from IFN beta-treated MS patients have been reported previously. We further explored the modulatory role of IFN beta-1a on the newly defined Th17 subset of CD4(+) T cells, which have been shown to be involved in mediating inflammatory responses in autoimmune disorders like RMS. Objective: To measure pharmacological response to IFN beta-1a and PEG-IFN beta-1a related to Th17 regulatory network in genomic samples from healthy volunteers. Methods: Whole blood RNA samples were collected from healthy volunteers enrolled in a phase 1 clinical study of PEG-IFN beta-1a, in which single doses of subcutaneous (SC) PEG-IFN beta-1a were administered at 3 dose levels and compared with intramuscular (IM) IFN beta-1a. Expression of 84 genes related to the Th17 regulatory pathway was probed before and after dosing of PEG-IFN beta-1a or IM IFN beta-1a. Purified RNA was reverse transcribed and tested in the RT2 Profiler PCR Array (SA Biosciences). Molecules analyzed at the mRNA level included cell surface proteins, chemokines, cytokines, cytokine receptors, and IFN beta-related signaling pathway molecules and transcriptional factors. Statistical significance was computed to understand the key players involved in mediating IFN beta-1a pharmacology. Results: Meaningful changes in the levels of many IFN-dependent gene transcripts (SOCS1, ISG20, JAK2) were detected, thus validating the sensitivity of the experimental analysis system. Significant upregulation of the IL-10 transcript, which has been linked to the likely shift to Th2-dominated response from a predominantly Th1 response, was observed in all groups. Modest IL-23A upregulation and significant chemokine (CCL1, CCL2, CCL7) upregulation were also observed. Conclusion: Use of similar PCR array in future studies to monitor the pharmacological effects of PEG-IFN beta-1a in RMS patients may enable better understanding of its molecular mechanisms of action and help to identify new biomarkers of efficacy for this therapeutic approach.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti, Farmacija, Biotehnologija

POVEZANOST RADA