Early treatment with heart failure drugs preserves cardiac and skeletal muscles in a mouse model of DMD

Transcription

1 Early treatment with heart failure drugs preserves cardiac and skeletal muscles in a mouse model of DMD Jill A. Rafael-Fortney, Ph.D. Associate Professor Dept. Molecular and Cellular Biochemistry (Physiology & Cell Biology, Cardiology) Director, Ohio State Biochemistry Program

2 What are Glucocorticoid and Mineralocorticoid Receptors? Closely related steroid hormone receptors Control gene expression Action can be modified by drugs that bind instead of steroid hormone 2

3 Prednisone and Spironolactone Prednisone is a glucocorticoid that binds to glucocorticoid receptors Spironolactone is an aldosterone analog that binds to mineralocorticoid and glucocorticoid receptors Eplerenone is an aldosterone analog that specifically binds mineralocorticoid receptors prednisone spironolactone 3

4 What do we know about spironolactone and eplerenone? Current ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults recommends aldosterone antagonists at Stage C of heart failure with continued ACEi recommended at Stage A 3 major large scale clinical trials with these drugs have demonstrated profound improvements in decreasing hospitalizations and increasing survival when added to the standard-of-care ACEi Randomized Aldactone Evaluation Study- RALES - spironolactone in New York Heart Association classes III-IV patients Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study- EPHESUS Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure -EMPHASIS-HF

5 5 A story of a DMD boy and his family, a cardiologist and a scientist working together...

6 DMD and utrophin/dystrophin-deficient mouse hearts show the same pattern of scarring with NORMAL ejection fraction 10 wk dko 14 yr old DMD pa0ent 6

7 Original questions: The cardiologist wondered... Since lisinopril/spironolactone is thought to be antifibrotic, can early treatment with these drugs prevent cardiomyopathy in DMD/BMD? Anecdotal data from the boy. Can we rigorously test in a dystrophic mouse model? The scientist wondered... Since fibrosis pathways are the same in dystrophic heart and skeletal muscles, can these drugs also prevent fibrosis in skeletal muscles? The boy and his family wondered... How can we help improve cardiac care for DMD patients? 7

8 Drug treatment significantly improves whole heart function in vivo cmri Strain Rate (endocard. circum. s - 1 )

9 Drug treatment improves heart histology Treated 20 week het 8 wk start Untreated 20 week het Treated 20 week het 4 wk start

10 Myocyte damage and MMP activity are significantly reduced by treatment

11 Drug treatment improves limb skeletal muscle function earlier treatment is most beneficial

12 Drug treatment improves respiratory skeletal muscle function earlier treatment is most beneficial

13 Ongoing myofiber damage is significantly reduced by treatment

14 Ongoing damage in cardiac and skeletal muscles is greatly reduced by early combinatorial drug treatment

15 Clinical Trial Underway in Ohio Early Treatment of Cardiomyopathy in DMD (clinicaltrials.gov ID: NCT ) Focus of study: Impact of medicines on heart function and muscle damage Most accurately measured with cardiac MRI 2 centers: Ohio State University (Columbus) and Cincinnati Children s Boys assigned to ACEI/ARB plus eplerenone or ACEI/ARB alone Randomized, double-blind trial design

16 In vivo Cardiac MRI Ex vivo Histology Normal Function Preclinical Scarà Less Scar with Treatment à Could earlier treatment with old drugs used to treat advanced heart failure work better?

17 Study Design Randomized, double-blind controlled trial of eplerenone vs. placebo in addition to background therapy that will include ACE inhibitor or ARB in all enrolled patients Hypothesis: patients randomized to eplerenone will experience - No decline in heart function at 12 months No increase in muscle damage at 12 months 8 boys enrolled; need 32 more

18 Enrollment Criteria Inclusion DMD confirmed by prior genotyping, age 7 years Normal EF / LGEpositive by CMR Ability to undergo cardiac MRI without sedation and follow breathholding instructions Exclusion Kidney problems Taking eplerenone or other drugs like it 18

19 Visits Baseline 1 month 3 months 6 months 9 months 12 months Cardiac MRI (at OSU or CCHMC) Follow-up labs (where convenient) X X X X X X Clinic visits X X X 19

20 In progress preclinical studies: 1. How does lisinopril-spironolactone compare to prednisone and does prednisone inhibit effects?- Funded by Cure Duchenne Untreated mdx mice Lisinopril + Spironolactone Losartan + Spironolactone Prednisolone Lisinopril + Spironolactone + Prednisolone Losartan + Spironolactone + Prednisolone Untreated normal controls 2. Is lisinopril, spironolactone, or both responsible for improvements in all 3 muscle types? - Funded by PPMD

21 Remaining critical questions required for optimal translation 1. Does spironolactone work through mineralocorticoid or glucocorticoid receptors and represent an improved version of prednisone? Required information for screening other shelved drugs for improved efficacy in DMD patients Will pave the way to identify responders and nonresponders to both prednisone and/or spironolactone/ eplerenone 2. What are the gene expression changes that lead to the functional improvement? Identification of additional therapeutic targets Identification of biomarkers for monitoring clinical efficacy 3. Does improved function persist over longer treatment periods with and w/o exercise?

22 Clinical trial questions? OSU: Dr. Subha Raman or Beth McCarthy, or CCHMC: Dr. Kan Hor or Lani Relucio, or clinicaltrials.gov

23 Funding Beckman Foundation Undergraduate Research Scholarship" NIH T32HL ; UNCF-Merck Postdoctoral Fellowship

24 24 Acknowledgements Kevin Schill" Jason Murray" Dawn Delfín, Ph.D. *" Eric Shultz" Raj Chimanji #" Ranjit Ganguly #! Tess Mays" " Subha Raman, M.D.! Tam Tran" " OSU Small Animal Imaging Core" " PPMD single drugs and timing" Paul Janssen, Ph.D." Ying Xu, Ph.D." Benjamin Canan, MPH" Jenna Stangland" Chris Martin! " BallouSkies: Original Drug Study " PPMD: Lisinopril v. Spironolactone" Cure Duchenne pred/losartan" " #Supported by Beckman Foundation Undergraduate Research Scholarship" *Supported by NIH T32HL ; UNCF-Merck Postdoctoral Fellowship"