Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy.

Fabry disease (FD) is a rare X-linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α-galactosidase. Gb3 deposits activate immune-mediated systemic inflammation, ultimately leading to life-threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP-1 and TNF-α cytokine levels were almost doubled in plasma from ERT-treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2-year period of continuous ERT. Apabetalone is a clinical-stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2-selective BETi, dose dependently reduced the production of MCP-1 and IL-12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2-selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2-selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials.

Evaluation of the quality of clinical data collection for a pan-Canadian cohort of children affected by inherited metabolic diseases: lessons learned from the Canadian Inherited Metabolic Diseases Research Network.

BACKGROUND: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. METHODS: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. RESULTS: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing). DISCUSSION: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

Regulatory Framework for Conducting Clinical Research in Canada.

Research in human subjects is at the core of achieving improvements in health outcomes. For clinical trials, in addition to the peer review of the results before publication, it is equally important to consider whether the trial will be conducted in a manner that generates data of the highest quality and provides a measure of safety for the participating subjects. In Canada, there is no definitive legislation that governs the conduct of research involving human subjects, but a network of regulations at different levels does provide a framework for both principal investigators and sponsors. In this paper, we provide an overview of the federal, provincial and institutional legislation, guidelines and policies that will inform readers about the requirements for clinical trial research. This includes a review of the role of the Food and Drug Regulations under the Food and Drugs Act and the Tri-Council Policy Statement (TCPS2), an overview of provincial legislation across the country, and a focus on selected policies from institutional research ethics boards and public health agencies. Many researchers may find navigation through regulations frustrating, and there is a paucity of information that explains the interrelationship between the different regulatory agencies in Canada. Better understanding the process, we feel, will facilitate investigators interested in clinical trials and also enhance the long-term health of Canadians.