Cardiomyopathy Due to a Lamin A/C Gene Mutation: Helping Your Heart Pump Again
“ARRY-371797 is potentially the first drug to act on the disease mechanisms as selective p38 mitogen-activated protein kinase (MAPK) inhibitor with the possibility to rescue heart damage.”
Genetic dilated cardiomyopathy is an inherited form of heart disease that is transmitted in an autosomal dominant manner. The prevalence of familial dilated cardiomyopathy is approximately 30% to 50% among patients with dilated cardiomyopathies.1 Dilated cardiomyopathy is a common phenotype associated with mutation of the Lamin A/C gene (LMNA gene) that is encoding the lamin A/C protein. Approximately 8% of the familial dilated cardiomyopathies are due to this gene mutation.2 Mutations in the LMNA gene can cause a variety of human diseases collectively known as laminopathies.3 The LMNA gene associated cardiomyopathy typically begins in mid-adulthood and is characterized by the enlargement of the left ventricle, causing reduced systolic performance that over time results in heart failure with poor prognosis and high mortality. Patients with familial dilated cardiomyopathy experience significant conduction system disease, malignant ventricular arrhythmias, shortness of breath, fatigue, and swelling of the legs. Currently, patients with LMNA only have the option to be treated with symptomatic and supportive therapies: beta-blockers, angiotensin-converting-enzyme inhibitors, aldosterone receptor antagonists, and diuretics. As there is no truly effective treatment, the only promising solution for most patients is heart transplantation.
ARRY-371797 is potentially the first drug to act on the disease mechanisms as selective p38 mitogen-activated protein kinase (MAPK) inhibitor with the possibility to rescue heart damage.4 It is currently the only molecule in active clinical development for LMNA associated cardiomyopathy.
“Therefore, selective inhibitors of p38 MAPK pathway signaling could potentially be used to treat humans with cardiomyopathy caused by LMNA mutations.”
Although, the structure–function relationships of the LMNA mutation at the cellular and protein level is not well understood, this mutation results in progressive replacement of the myocardium (heart muscle) with fat and fibrous tissue. Research studies have shown elevation in p38 mitogen-activated protein (MAP) kinase signaling in hearts of mice and humans with cardiomyopathy caused by LMNA mutations. P38 MAPK kinase is a key enzyme responsible for prostaglandin synthesis and for the production of proinflammatory cytokines, including tumor necrosis factor-alpha and interleukin.4 Further, the activation of the inflammatory cytokine cascade by the p38 MAPK pathway are implicated in several cardiovascular diseases. Therefore, selective inhibitors of p38 MAPK pathway signaling could potentially be used to treat humans with cardiomyopathy caused by LMNA mutations.4
In early cellular studies, ARRY-371797, was able to recover the actin network in cardiomyocytes (heart cells) and to restore biomechanical properties in ventricular cardiomyocytes from rat LMNA mutation by selective inhibition of the p38 MAPK pathway.4 Based on the beneficial effects of ARRY-371797 on left ventricular diameters in the mouse models of cardiomyopathy caused by LMNA mutations, Array BioPharma conducted a pilot Phase 2 trial of ARRY-371797 in patients with cardiomyopathy caused by LMNA mutations.5,6 This Phase 2 pilot study was designed to test the effectiveness of ARRY-371797 over a 48-week treatment period. The primary outcome measure assessed the efficacy in terms of change from baseline in 6-minute walk test after 12 weeks; secondary outcome measures included myocardial function and safety throughout the 48 week of the study.6
Following encouraging results from the Phase 2 clinical trial in 12 patients with LMNA, that showed clinical testing was advanced into Phase 3 trial in 2018.7 The ongoing Phase 3 is a multinational, randomized, placebo-controlled investigation of 400 mg of ARRY-371797 administered orally twice daily over 24 weeks in 160 patients with symptomatic dilated cardiomyopathy due to a confirmed lamin A/C gene mutation.7 Patients that complete 24 weeks of treatment with improvements in the 6-minute walk test, designed to assess exercise tolerance, may qualify to receive open-label treatment with ARRY-371797 for an extended period of time.7
If the results from this trial, expected in late 2020, are positive, this would represent the first possibility to rescue the inherited biomechanical defect of the heart in patients with this rare, degenerative cardiovascular disease caused by mutations in the LMNA gene. If pharmacological inhibition of p38 MAPK is successful, this novel approach can also be used as prophylactic treatment in asymptomatic patients with LMNA mutations and in a variety of other laminopathies such as skeletal Emery–Dreifuss muscular dystrophy and Barraquer–Simons syndrome.
Mila Pastrak
Works Cited:
1. Mcnally EM, Mestroni L. Dilated Cardiomyopathy. Circulation Research. 2017;121(7):731-748. doi:10.1161/circresaha.116.309396.
2. Muchir A, Wu W, Choi JC, et al. Abnormal p38 mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics. 2012;21(19):4325-4333. doi:10.1093/hmg/dds265.
3. Worman HJ. Cell signaling abnormalities in cardiomyopathy caused by lamin A/C gene mutations. Biochemical Society Transactions. 2017;46(1):37-42. doi:10.1042/bst20170236.
4. Laurini E, Martinelli V, Lanzicher T, et al. Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins. Cardiovascular Research. 2018;114(6):846-857. doi:10.1093/cvr/cvy040.
5. Muchir A, Wu W, Choi JC, et al. Abnormal p38 mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics. 2012;21(19):4325-4333. doi:10.1093/hmg/dds265.
6. A Study of ARRY-371797 in Patients With LMNA-Related Dilated Cardiomyopathy - Full Text View. Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02057341. Published May 16, 2017.
7. A Study of ARRY-371797 in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation - Full Text View. Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03439514. Published January 2, 2020.
Cite this article:
Pastrak M., Rashid S., Kord D., Pavithran N. Cardiomyopathy Due to a Lamin A/C Gene Mutation: Helping Your Heart Pump Again. Illustrated by S. Montakhaby Nodeh. Rare Disease Review. November 2020. DOI: 10.13140/RG.2.2.18256.94722
