Silvia G Priori MD PhD

Transcription

1 Novel therapies for the long QT syndrome. Silvia G Priori MD PhD Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri Pavia, Italy and Leon Charney Division of Cardiology, Cardiovascular Genetics Program, Langone Medical Center, New York University School of Medicine, New York, USA

2 Long QT syndrome Long QT syndrome with extracardiac phenotypes Timothy Andersen Jervell and LangeNielsen Brugada syndrome Catecholaminergic Polymorphic Ventricular Tachycardia Short QT syndrome Channelopathies Progressive conduction defect

3 Contribution of genetics to the management of arrhythmogenic diseases Molecular diagnosis allows screening of family members and identification of individuals at risk Genotype/Phenotype correlations may guide management Understanding of pathophysiology helps devise novel therapies

4 Contribution of genetics to inherited arrhythmogenic diseases 15 years after the discovery of the first genes for LQTS, the field is still rapidly developing Understanding of molecular mechanisms of diseases is impacting risk stratification and management The focus on development of new therapies is leading to the identification of the new roles for old drugs

5 Disease management in the genetic era: Long QT Syndrome

6 D2 V2

7 LONG QT SYNDROME GENES >90%

8 Difetti funzionali dei canali che trasportano potassio causano per lo più un perdita di funzione (meno potassio in Uscita dalla cellula) e ritardano La ripolarizzazione cardiaca Prolungando il potenziale d azione Il tratto QT dell ECG.

9 The KEY LQTS genes Gene Locus Protein % of Disease Long QT Syndrome (LQTS) KCNQ1 (LQT1) 11p15.5 KCNH2 (LQT2) SCN5A (LQT3) 7q35-q36 3p21 I Ks potassium channel alpha subunit (Kv7.1) 30-35% I Kr potassium channel alpha subunit (Kv11.1 or herg) 25-40% Cardiac sodium channel alpha subunit (NaV1.5) 5-10% Europace. 2011;13:

10 Cumulative Survival (%) Event-free survival according to QTc QTc <446 QTc P< QTc Quartiles 1 st 2 nd 3 rd 4 th Age (years) QTc QTc > 500 msec Priori SG et al NEJM 2003

11 Cumulative Survival (%) Survival in LQTS according to genotype p=0.007 Genotype LQT1: LQT2: LQT3: LQT1 LQT2 LQT Age (years) Priori SG et al NEJM 2003

12 Cardiac event free survival Cardiac Events on Beta-blockers in LQTS LQT LQT3 LQT p< Follow up (years) Priori et al. JAMA 2004

13 Molecular Cardiology Laboratories, Fondazione

14 Molecular Cardiology Laboratories, Fondazione

15 LQTS-SCN5A Mutations: EP Consequences Sustained I Na current in LQT3 mutations

16 Pharmacological modulation of an SCN5A mutation 0 pa τ s =14 ms τ s =15 ms 50 pa Baseline 50 ms Sodium channel blockers (specific action on Isus?)

17 In 1996 we hypothesized that sodium channel blockers may reverse APD Prolongation induced by late INa We used a toxin called Anthopleuring that increases INa to test out hypothesis APD ANTHOPLEURIN DOFETILIDE prologation A= Control B= Anthopleurin or Dofetilide C= Mexiletine Priori et al. Circulation Research. 1996;

18 Mexiletine inhibits late sodium current Yuanfeng Gao et al. Circ Arrhythm Electrophysiol. 2013;6: Copyright American Heart Association, Inc. All rights reserved.

19 QTc (ms) JTc (ms) Our first experience with mexiletine in patients in Control Na Channel Blocker 280 Control Na Channel Blocker

20 May we predict response to Mexiletine in LQT3? The degree of QTc interval shortening in Mexiletine treated patients is highly variable: it ranges between 0 to 15% (i.e. in a pt with QTc 500 may normalize QTc!). Criteria to identify responders are lacking.

21 R1626P Sensitive to Mexiletine Before QTc 480ms After QTc 420ms P1332L QTc 570ms QTc 493ms P1332L QTc 506ms QTc 455ms

22 Insensitive to Mexiletine Baseline QTc 600ms Mexiletine QTc 570ms S941N QTc 607ms QTc 607ms M1652R

23 Steady state inactivation Normalized Current p< 0.05 PL vs. W T p< 0.01 RP vs. W T p< 0.01 M R vs. W T NS SN vs. W T Prepulse potential(mv) WT P1332L M1652R S941N R1626P INa inactivates faster in the Presence of Mexi in the sensitive mutations. Ruan Yangefei et al Circulation. 2007

24 A new compound for LQT3 treatment called GS-6615 / ELECLAZINE is a more selective blocker of late sodium current Dr ZAREBA s DATA

25 Baseline GS-6615/eleclazine (18/06/2015) Day V5 V5 RR 1020 ms; QT 470 ms; QTc 467 ms RR 1070 ms; QT 400 ms; QTc 391 ms Night V5 V5 RR 1050 ms; QT 480 ms; QTc 472 ms RR 810 ms; QT 370 ms; QTc 397 ms

26 Read-through premature stop codons llen M. Welch et al PTC124 targets genetic disorders caused by nonsense mutations Nature 2007; 447, proof of concept Ryan J Drugs (2014) 74: Ataluren: First Global Approval 2014 approval for Duchenne

27 Ataluren allows production of a normal protein reading over a stop codon

28 Truncations of HERG in LQT2 patients

29 Gentamycin to rescue HERG truncations

30 Comparative read-through activity of Ataluren, G418, Gentamycin and Tobramycin Yu H et al International Journal of Molecular Medicine 33: , 2014 Aminoglycosides and PTC124 have different read-through efffects Rescue efficiency reduced in mutations in the N-terminal PTC is less effective than aminoglycosides Search for HERG specific molecules in ongoing

31 Q&A Which of the following is true? 1. Mexiletine shortens QT interval in LQT3 patients bacause it blocks the late sodium current 2. LQT3 patients can shorten the QT interval in the presence of mexiletine because the drug prolongs action potential duration 3. LQTS patients prolong QT interval when receiving a sodium channel blocker

32 Q&A Which of the following is false? 1. Ataluren is a new drug that corrects most genetic defects in long QT syndrome 2. Ataluren allows the avoidance of genetically mediated truncation of proteins 3. Ataluren prevents alternative splicing and therefore is able to restore normal QT interval

33 CONCLUSIONS The discovery of mutations associated with inherited arrhythmias has stimulated a very important advancement in the understanding of these diseases. The understanding of molecular mechanisms opens the doors to the introduction of novel therapies. Gene-specific therapies represent the new frontier of pharmacology of channelopathies. Promising novel approaches are being developed for the most severe forms of LQTS with partial response to beta-blockers.

34 Carlo Napolitano Raffaella Bloise Nicola Monteforte Rossana Bongianino Mirella Memmi Marco Denegri Francesco Lodola Alessandra Vollero Nian Liu Yanfei Ruan Nicoletta Rizzi Massimo Santoro