Key Dates

Related Announcements

• December 18, 2025 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-25-301.

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

Patients with muscular dystrophies and their caregivers, including families and clinical teams, face significant challenges. These individuals often experience progressive difficulties in breathing and sleeping, along with decreased exercise tolerance due to cardiorespiratory insufficiency. This takes a substantial toll on them and their families. The purpose of this NOSI renewal is to enhance basic, translational, and clinical research in the cardiorespiratory and sleep complications associated with muscular dystrophies. The goals include elucidating phenotypes, optimizing metrics for early diagnosis, refining therapies such as gene therapy delivery to cardiac and respiratory muscles, and exploring mechanisms and treatment strategies for sleep-disordered breathing (SDB).

Muscular dystrophies are a heterogeneous group of congenital diseases, including Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and myotonic dystrophy (DM), all leading to progressive weakness and cardiorespiratory decline. Advances in clinical care have increased the lifespan for some conditions like DMD; however, progressive cardiomyopathy, conduction defects, subendocardial fibrosis, and systolic dysfunction often lead to heart failure. Acute respiratory failure from pneumonia, aspiration events, and acute respiratory distress syndrome (ARDS), along with chronic respiratory insufficiency requiring invasive and non-invasive support, remain leading causes of mortality and morbidity. Understanding cardiopulmonary interactions in the context of progressive obstructive and/or restrictive respiratory disorders is crucial to elucidation of the cardiopulmonary phenotype.

SDB affects up to 75% of patients with muscular dystrophies, with its incidence varying among subtypes. It often results from hypoventilation due to progressive muscle weakness, including the strength needed to maintain upper airway patency, leading to obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) devices can ameliorate hypoxia and hypercapnia, improving quality of life and longevity. However, the prevalence and trajectories of SDB across dystrophies, and the optimal timing for CPAP initiation, have not been extensively characterized. Central sleep apnea (CSA) can also be common, but its prevalence, developmental trajectory, and treatment options are less characterized. While CPAP may be effective for CSA, systematic studies are limited.

Advances in gene editing, such as CRISPR-Cas technology, hold promise for treating DMD. Further research is needed to understand the implications of gene therapy on cardiac and pulmonary recovery, given that weakness begins in mid-adolescence, leading to progressive pulmonary limitation, while cardiac failure may develop in the 30s and 40s. In other dystrophies, too, the trajectory of cardiorespiratory decline is variable. Detailed phenotyping could elucidate the trajectory and early predictors of decline in cardiorespiratory function. While animal models provide insights into cardiac phenotypes and impact of gene therapy, human studies are essential due to differences in heart size, rate, and metabolism. Current challenges include developing biomarkers for early detection, understanding cardiac delivery and toxicity of gene therapy, and characterizing fibro-fatty cardiomyocyte replacement.

Pulmonary phenotyping and early intervention can delay mortality and improve Health-Related Quality of Life (HRQOL). Strategies such as incentive spirometry, inspiratory muscle strength training, positive pressure ventilation, and mucociliary clearance can maximize lung function and slow decline. Developing biomarkers to predict pulmonary decline earlier in the disease course is critical. This NOSI will further research to identify optimal metrics for evaluating the impact of existing interventions on pulmonary function.

Research is needed to better understand upper airway obstruction and central ventilatory control mechanisms, given the heterogeneity in pulmonary decline among different dystrophies and individuals. Racial and ethnic disparities in outcomes highlight the need for equitable care and research addressing these disparities, and for encouraging participation from understudied populations.

This NOSI is a call for studies that will address barriers to participation in research by NIH-designated populations that experience health disparities and/or by other understudied populations living with muscular dystrophies by employing strategies and resources to reduce obstacles and encourage outreach to these populations living with muscular dystrophies, as described on the website, https://www.mdcc.nih.gov/strategies-promote-diversity-muscular-dystrophy-research-participation. To enhance awareness and participation in research among understudied populations, resources built by NIH-wide Community Engagement Alliance (CEAL) against COVID-19 Disparities could also be leveraged by investigators in the muscular dystrophy space, building upon proven strategies.

Research examples include, but are not limited to:

• Genetic and environmental factors contributing to heterogeneity of outcome
  • Research on better implementation and adherence to current guidelines for cardiorespiratory evaluation and care
  • Understanding the impact of disparity in access to health care (poverty, rural areas, racial disparity and ethnic minorities, for example) on cardiopulmonary outcomes and quality of life
• Testing and therapies
  • Development of biomarkers/scores to predict and monitor cardiac and pulmonary decline
  • Development of biomarkers for early detection, diagnosis, and outcome measures for therapeutic development for cardiovascular complications, such as cardiomyopathy and arrhythmias
  • Small molecules to reduce cardiomyopathy and heart failure
  • Optimization of pulmonary function testing and devices in humans with muscular dystrophies
  • Upper airway obstruction and sleep apnea in adults and children 
  • Optimization of home ventilation strategies
  • Adherence to inspiratory and expiratory muscle strength training
  • Longitudinal studies to follow impact of timely respiratory care, including treatments for sleep-disordered breathing associated with the dystrophies
  • Research on training caregivers
• Mechanistic and Translational Science
  • Markers of respiratory decline in animal models and humans
  • Cardiopulmonary interactions in animal models and humans
  • Dystrophy-related effects on central control of ventilation and its role in sleep-disordered breathing
  • Mechanisms of diaphragmatic dysfunction in the muscular dystrophies
  • Targeted delivery of gene therapies to the diaphragm in animal models and following their effect on respiratory function
  • Targeted delivery of gene therapies to the heart
  • Mechanisms of the progression of fibro-fatty replacement in cardiomyopathy
  • Cardiac toxicity from the vectors or the therapeutic genes in gene therapy and Long-term studies to understand the chronic effects of gene therapy on the heart

Application and Submission Information

Submit applications for this initiative using the following Notice of Funding Opportunity (NOFO) or any reissue of this announcement through the expiration date of this notice.

• PA-25-301 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and in the NOFO used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-HL-24-036” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Aruna Natarajan, MD, PhD
National Heart Lung and Blood Institute (DLD, NHLBI) 
Telephone: 301-827-0180
Email: [email protected]

Huiqing Li, MD, PhD
National Heart Lung and Blood Institute (DCVS, NHLBI) 
Telephone: 301-435-0554
Email: [email protected]

Lawrence Baizer, PhD
National Heart Lung and Blood Institute (NCSDR, NHLBI) 
Telephone: 301-480-7481
Email: [email protected] 

Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Financial/Grants Management Contact(s)

Financial/Grants Management Contact(s)

Kimberly Watkins
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-827-8054
Email: [email protected]