Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

McDonald, Craig; Marbán, Eduardo; Hendrix, Suzanne; Hogan, Nathaniel J.; Smith, Rachel; Eagle, Michelle; Finkel, Richard S.; Tian, Chengming; Janas, Joanne; Harmelink, Matthew; Varadhachary, Arun S.; Taylor, Michael D.; Hor, Kan N.; Mayer, Oscar H.; Henricson, E.; Furlong, Pat; Ascheim, Deborah D.; Rogy, Siegfried; Williams, Paula; Marbán, Linda; Butterfield, Russell J.; Connolly, Anne M.; Muntoni, Francesco; Joyce, Nanette C.; Evans, Maya; Abedi, Mehrdad; Surampudi, Prasanth; Jhawar, Sanjay; Dayan, Jonathan; Anthonisen, Colleen; Goude, E.; Nicorici, Alina; Sarwary, Omaid; Prasad, P. V. Devi; Baek, Jayoon; Newton, Andrew D.; Johnson, Hannah; Kusmik, Kyle; Filar, Lauri; Edmondson, Angie; Rybalsky, I.; Chouteau, Wendy A; Giordano, Anthony F.; Rodríguez, Aixa; Anderson, Kristan; Wezel, Germaine; Vega, Melisa; Duke, Julie; Collado, Jorge; Civitello, Matthew; Wells, Julie; Pyzik, Erika; Rehborg, Rebecca; Brown, Michelle; Eyk, Jennifer E. Van; Rogers, Robert W.

doi:10.1016/s0140-6736(22)00012-5

Cited by 50 publications

(34 citation statements)

References 29 publications

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“…Interestingly, the intraarterial and intravenous delivery of cardiomyocytes representing the striated muscles and cardiosphere-derived cells confirmed improvement of cardiac function as well as elicited the off-cardiac effects confirmed by improvement of the upper limb function, thus supporting the rationale for systemic delivery of cells of muscle tissue origin [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 91%

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

Siemionow

Langa

Brodowska

et al. 2022

Stem Cell Rev and Rep

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Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in dystrophin encoding gene, causing progressive degeneration of cardiac, respiratory, and skeletal muscles leading to premature death due to cardiac and respiratory failure. Currently, there is no cure for DMD. Therefore, novel therapeutic approaches are needed for DMD patients.We have previously reported functional improvements which correlated with increased dystrophin expression following administration of dystrophin expressing chimeric (DEC) cells of myoblast origin to the mdx mouse models of DMD.In the current study, we confirmed dose-dependent protective effect of human DEC therapy created from myoblasts of normal and DMD-affected donors, on restoration of dystrophin expression and amelioration of cardiac, respiratory, and skeletal muscle function at 180 days after systemic-intraosseous DEC administration to mdx/scid mouse model of DMD. Functional improvements included maintenance of ejection fraction and fractional shortening levels on echocardiography, reduced enhanced pause and expiration time on plethysmography and improved grip strength and maximum stretch induced contraction of skeletal muscles. Improved function was associated with amelioration of mdx muscle pathology revealed by reduced muscle fibrosis, reduced inflammation and improved muscle morphology confirmed by reduced number of centrally nucleated fibers and normalization of muscle fiber diameters. Our findings confirm the long-term systemic effect of DEC therapy in the most severely affected by DMD organs including heart, diaphragm, and long skeletal muscles.These encouraging preclinical data introduces human DEC as a novel therapeutic modality of Advanced Therapy Medicinal Product (ATMP) with the potential to improve or halt the progression of DMD and enhance quality of life of DMD patients. Graphical Abstract Human DEC as a novel therapeutic modality with the potential to improve or halt progression of the DMD disease and enhance quality of life of DMD patients. Graphical abstract represents manufacturing process of the human DEC therapy for the future clinical applications. 1. We report the long-term efficacy of human DEC therapy resulting in increased dystrophin expression and reduced mdx muscle pathology after systemic-intraosseous administration of human Dystrophin Expressing Chimeric (DEC) Cells to the mdx/scid mouse model of DMD. 2. Systemic administration of human DEC therapy resulted in amelioration of cardiac, respiratory and skeletal muscle function as confirmed by echocardiography, plethysmography and standard muscle strength tests respectively. 3. We introduce human DEC as a novel Advanced Therapy Medicinal Product (ATMP) for future clinical application in DMD patients.

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Section: Discussionmentioning

confidence: 91%

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

Siemionow

Langa

Brodowska

et al. 2022

Stem Cell Rev and Rep

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“…CDCs act by secreting extracellular vesicles known as exomes, which alter the expression profile of macrophages and reprogram fibroblasts, thus reversing the proinflammatory and -fibrotic phenotype in DMD. For sustained efficacy, treatment with CAP-1002 must be repeated every 3 months as CDCs perish over time (McDonald et al, 2022). Currently, there is one Ph3 trial registered at ClinicalTrials.gov to evaluate the safety and efficacy of CAP-1002.…”

Section: Cell Therapymentioning

confidence: 99%

“…Results showed that the HOPE-2 trial met its primary endpoint of Mid-level Performance of Upper Limb (mid-PUL) v1.2, by slowing decline by 71% at month 12. Furthermore, patients treated with CAP-1002 demonstrated improvements in various measures of cardiac function and structure, suggesting clinically relevant slowing of disease progression (McDonald et al, 2022). Capricor is currently planning a pivotal Ph3 study (HOPE-3, NCT05126758) to evaluate the safety and efficacy of CAP-1002 in up to 68 DMD patients with reduced ability to walk/run.…”

Section: Cap-1002mentioning

confidence: 99%

Drug development progress in duchenne muscular dystrophy

et al. 2022

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Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space.

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“…Clinical studies have demonstrated that allogeneic CDCs play immune modulatory, anti-fibrotic and regenerative roles in DMD and heart failure and are well tolerated in severely affected patients with DMD, but infusion-related hypersensitivity reactions may occur when allogeneic CDCs were sequential intravenous infusions [ 86 , 87 , 88 ]. The intravenous delivery of CDCs into mdx mice can reduce proinflammatory cytokines and alter the expression of genes related to oxidative stress, inflammation, mitochondrial integrity and muscle regeneration by secreting exosomes containing various non-coding RNA and active substances such as mir-148a.…”

Section: Several Strategies Are Currently Under Development To Overco...mentioning

confidence: 99%

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy

Song

2022

Genes

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Gene therapy using the adeno-associated virus (rAAV) to deliver mini/micro- dystrophin is the current promising strategy for Duchenne Muscular Dystrophy (DMD). However, the further transformation of this strategy still faces many “bottlenecks”. Most gene therapies are only suitable for infants with strong muscle cell regeneration and immature immune system, and the treatment depends heavily on the high dose of rAAV. However, high-dose rAAV inevitably causes side effects such as immune response and acute liver toxicity. Therefore, how to reduce the degree of fibrosis and excessive immune response in older patients and uncouple the dependence association between therapeutic effect and high dose rAAV are crucial steps for the transformation of rAAV-based gene therapy. The article analyzes the latest research and finds that the application of utrophin, the homologous protein of dystrophin, could avoid the immune response associated with dystrophin, and the exploration of methods to improve the expression level of mini/micro-utrophin in striated muscle, combined with the novel MyoAAV with high efficiency and specific infection of striated muscle, is expected to achieve the same therapeutic efficacy under the condition of reducing the dose of rAAV. Furthermore, the delivery of allogeneic cardio sphere-derived cells (CDCs) with anti-inflammatory and anti-fibrotic characteristics combined with immune suppression can provide a continuous and appropriate “window period” for gene therapy. This strategy can expand the number of patients who could benefit from gene therapy.

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Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 50 publications

References 29 publications

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

Drug development progress in duchenne muscular dystrophy

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy

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