Also from that book of abstracts you linked to - maybe only new to me

( Looks like there was some good news on the Fabry disease side too.)

P0068APABETALONE, A CLINICAL STAGE BET INHIBITOR,REDUCES THE PRO-INFLAMMATORY RESPONSE IN PBMCS FROM FABRY DISEASE PATIENTS ON ERT THERAPY

Li Fu1, Sylwia Wasiak1, Brooke Rakai1, Stephanie Stotz1, Norman Wong1,Jan Johansson2, Michael Sweeney2, Connie Mohan3, Aneal Khan3,4,Ewelina Kulikowski11Resverlogix, Calgary, Canada,2Resverlogix, San Francisco, United States of America,3Cumming School of Medicine, Alberta Children’s Research Institute, University ofCalgary, Calgary, Canada and4Professor of Medical Genetics and Pediatrics, Universityof Calgary

Background and Aims:  Fabry disease (FD) is a rare X-linked recessive genetic disordercaused by mutations in thea-galactosidase A gene. Absence or defects of this lysosomalenzyme lead to globotriaosylceramide (Gb3) accumulation. Gb3 disrupts basic cellularmetabolic processes, inducing oxidative stress and promoting inflammation.Systemically, Gb3 accumulation leads to organ damage throughout the body with anincrease in renal, cardiac, cerebrovascular and skin complications. Enzyme replacementtherapy (ERT) is current standard of care. This therapy may reduce Gb3 deposits butthe impact on cardiac and kidney function is unclear based on the limited studies.Further, ERT is less effective in the late phases of FD, partially due to the developmentof uncontrolled inflammation and fibrosis.

Apabetalone is a clinical stage orally admin-istered bromo and extra terminal domain inhibitor (BETi) that has beneficial effects onvascular inflammation and vascular calcification through an epigenetic pathway. Basedon its mechanism of action and impact on multiple disease drivers in both preclinicaland clinical studies, apabetalone has therapeutic potential to modulate inflammationin FD patients on ERT therapy.

Method:   PBMCs and neutrophils were isolated from fresh blood of FD patients6ERTtherapy using density gradient centrifugation. The baseline immune status of PBMCswas compared in naı ̈ve FD patients (without ERT, n=3) and ERT treated patients(n=8) via flow cytometry. PBMCs or neutrophils from ERT patients were treated exvivo with 5mMor20mM apabetalone6LPS stimulation. Expression of key pro-inflam-matory mediators was analyzed with real time quantitative PCR. The production ofreactive oxygen species (ROS) in neutrophils was assessed by flow cytometry.

Results:   The PBMC inflammatory profile in baseline showed monocytes from ERTpatients produced lower amounts of pro-inflammatory mediators (TNFaand IL6)than naı ̈ve patients (60%, trending p0.06 and p0.08 respectively). However, sur-face abundance of CCR2, a chemokine receptor for the MCP1 chemokine that pro-motes monocyte recruitment to local inflamed tissue during inflammatory process,was2-fold greater on monocytes from ERT subjects than the naı ̈ve controls (trendingp0.06). Gene expression ofMCP1was approximately 5-fold higher in PBMC fromERT patients versus naı ̈ve controls (p=0.01). In response to ex vivo LPS stimulation, PBMCs from FD patients on ERT showed a robust induction of pro-inflammatoryresponses with increases in gene expression of MCP1, IL12B, TNFA and IL6.

Ex vivo treatment with apabetalone (5mM) blocked the LPS-induction of MCP1gene expres-sion (90%, p<0.0001), and suppressed the upregulation ofIL12B,TNFA and IL6 by 85%, 27% and 17%, respectively (p<0.0001,p=0.04,p=0.004). In response to LPS stim-ulation, neutrophils induced reactive oxygen species (ROS), an indicator of oxidativedamage caused by intracellular Gb3 deposit in FD patients, by 6 fold. Apabetalone treatment reduced this induction by 32% and 62% at 5mM and 20mM, respectively (p=0.01, p=0.0007).

Conclusion: Monocytes from FD patients on ERT therapy display an enhanced expres-sion of the CCR2-MCP-1 axis as compared to naı ̈ve controls, indicating the potentialfor immune cell tissue infiltration and local inflammation. Apabetalone counters thisincrease by preventing MCP1gene transcription. Apabetalone also reduces PBMCmediated pro-inflammatory gene transcription (TNFA,IL12B,IL6) and neutrophilmediated ROS production in response to LPS stimulation. Therefore, apabetalonetreatment may reduce pathological inflammation in FD patients and thus complement ERT to optimize patient outcomes, which will be tested further with warranted clinicalstudies