Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of
Maria Siemionow1,2, M Malik3, P Langa3
1Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland. siemiom@hotmail.com.
Abstract:
Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MBwt/MBmdx) and mesenchymal stem cells (MBwt/MSCmdx) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 106) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 -MBwt/MBmdx and 5.22% ± 1.10 - MBwt/MSCmdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.
Insights
Duchenne Muscular Dystrophy (DMD) patients can benefit from Dystrophin Expressing Chimeric Cells (DEC) therapy. This novel approach improves cardiac function and muscle regeneration by delivering dystrophin to damaged heart and muscle tissues.
Area of Science:
- Regenerative Medicine
- Cardiovascular Research
- Genetics and Molecular Biology
Background:
- Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle weakness and degeneration.
- Cardiac dysfunction is a primary cause of mortality in DMD patients, necessitating effective therapeutic strategies.
- Current treatments for DMD are limited, highlighting the need for innovative approaches to cardiac protection and muscle repair.
Purpose of the Study:
- To evaluate the efficacy of Dystrophin Expressing Chimeric Cells (DEC) in improving cardiac function in a mouse model of DMD.
- To investigate the potential of DEC derived from myoblasts (MB) and mesenchymal stem cells (MSC) for therapeutic benefit in DMD.
- To assess dystrophin expression and cardiac function post-transplantation of DEC.
Main Methods:
- Systemic intraosseous injection of DEC (MBwt/MBmdx and MBwt/MSCmdx) into mdx mice, a model for DMD.
- Echocardiography was performed at 30 and 90 days post-transplantation to assess cardiac function (ejection fraction, fractional shortening).
- Dystrophin expression levels in cardiac muscle tissue were quantified at 90 days post-transplant.
Main Results:
- DEC transplantation led to a significant increase in dystrophin expression in the cardiac muscles of mdx mice compared to controls.
- Improved cardiac function, evidenced by enhanced ejection fraction and fractional shortening, was observed in DEC-treated mice at 90 days post-transplantation.
- Both myoblast- and MSC-derived DEC demonstrated therapeutic effects, suggesting a combined benefit of dystrophin delivery and immunomodulatory properties.
Conclusions:
- DEC therapy is a feasible and effective strategy for protecting cardiac function and promoting muscle regeneration in DMD.
- This novel approach offers a promising therapeutic avenue for addressing the cardiac complications associated with Duchenne Muscular Dystrophy.
- The combination of myoblasts and mesenchymal stem cells within DEC provides a multifaceted therapeutic potential for DMD treatment.
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