Johns Hopkins University

Cedars-sinai Medical Center

Toshiba Medical Systems Corporation

Capricor, Inc.

Eduardo Marban

Brian O'Rourke

J Kevin Donahue

Ronald A Li

Tian Xue

Suk-Ying Tsang

Hee Cheol Cho

Romain Gallet

Mark Amin Aminzadeh

Mitsushige Murata

Albert Clark Lardo

Takashi Ichihara

Jennifer E Van Eyk

Joao A C Lima

Koichi Nagata

Richard T George

Luis Rodriguez-Borlado

Ke Cheng

Ahmed Ibrahim

Russell Thomas Rogers

Christopher Stewart Sakoda

Eugenio Cingolani

Saravana Kanagavelu

Jennifer Moseley

David C Johns

Travis Antes

Masaharu Akao

Lilian Grigorian

John H Lawrence

Heecheol Cho

James Dawkins

Maria Roselle Abraham

Heart failure with preserved ejection fraction (HFpEF) is a disease condition characterized by heart failure (HF) signs and symptoms, but with normal or near normal left ventricular ejection fraction (LVEF) and is not responsive to standard therapy for treatment of HF. Described herein are compositions and methods related to use of cardiosphere derived cells (CDCs) and their exosomes to improve left ventricular structure, function and overall outcome. Administration of CDCs led to improved LV relaxation, lower LV end-diastolic pressure, decreased lung congestion and enhanced survival. Lower risk of arrhythmias in HFpEF was also observed following CDC administration. Improvement of diastolic dysfunction following administration of CDC-derived exosomes was observed, along with decreased mortality. In view of these salutary effects, CDCs and CDC-derived exosomes are beneficial in the treatment of HFpEF.

Cardiosphere-derived cells and exosomes secreted by such cells in the treatment of heart failure with preserved ejection fraction

Some embodiments provide a method of treating skeletal muscular myopathy, e.g., Duchenne muscular dystrophy (DMD), with cardiosphere-derived cells (CDCs), wherein a therapeutically effective amount of CDCs is delivered to a targeted dystrophic skeletal muscle. Some embodiment enable delivery of a therapeutically effective amount of CDCs via intramuscular injection directly at a skeletal muscle or systemic administration, intravenous injection, in a single dose or multiple doses, to treat a targeted dystrophic skeletal muscle. Some embodiments provide a method for improving exercise capabilities in DMD patients. Additional embodiments relate to exosome, mediated transfer of noncoding RNAs ameliorates Duchenne muscular dystrophy by restoring dystrophin in heart and skeletal muscle. Delivery of noncoding RNA species found in CDC-derived exosomes mimics the ability of CDCs and CDC-derived exosomes to increase dystrophin protein levels.

Methods and compositions for treating skeletal muscular dystrophy

The present application relates to methods and compositions for treating diseased or damaged cardiac tissue comprising regenerative cells harvested from donor cardiac tissue. In one embodiment, regenerative cells are harvested from an allogeneic source and after administration result in increased viability and/or functional improvement of damaged or diseased cardiac tissue.

Compositions comprising cardiosphere-derived cells for use in cell therapy

Several embodiments relate to engineered extracellular vesicles (EVs) using the membrane cloaking platform technology described herein, the cloaking imparting to the EVs enhanced delivery to tissues of interest, such as damaged or dysfunctional tissue. Several embodiments relate to engineering exosomes derived from cardiosphere-derived cells (CDCs) using the membrane cloaking platform technology described herein to confer enhanced tissue homing specificities, thereby leading to repair and regeneration at sites of injury. Uses of engineered EV compositions to treat diseases are also provided for in several embodiments.

Engineered extracellular vesicles for enhanced tissue delivery

Described herein are compositions and methods related to use of cardiosphere-derived cells and their extracellular vesicles, such as exosomes and microvesicles, for achieving anti-aging and rejuvenation. This includes discoveries for effects on heart structure, function, gene expression, and systemic parameters. For animal studies, intra-cardiac injections of neonatal rat CDCs was compared to in old and young rats including evaluation of blood, echocardiographic, haemodynamic and treadmill stress tests. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or cardiosphere derived cell (CDC) derived exosomes (CDC-XO) from pediatric donors. CDCs and CDC-XOs were capable of effectuating youthful patterns of gene expression in the hearts of old, along with a variant of physiological and function benefits, including elongation of telomere length. Together, these results indicate capacity of CDCs and CDC-XO to ward off the effects of aging through rejuvenation.

Cardiosphere-derived cells and their extracellular vesicles to retard or reverse aging and age-related disorders

Described herein are compositions and techniques related to generation and therapeutic application of cardiosphere-derived cells (CDCs) and CDC-derived exosomes. These cells and their secreted vesicles contain a unique milieu of biological factors, including cytokines, growth factors, transcription factors, nucleic acids including non-coding nucleic acids such as microRNAs, that serve to initiate and promote many therapeutic effects. Exosomes and their 'cargo' contents, such as microRNAs can favorably modulate apoptosis, inflammation and fibrosis in the injured heart. Thus, CDC-derived exosomes represent a novel 'cell-free' therapeutic candidate for tissue repair.

Cardiosphere-derived cells and exosomes secreted by such cells in the treatment of muscular dystrophy

Described herein are compositions and methods related to use of exosomes, including cardiosphere derived cell (CDC)-derived exosomes for treatment and prevention of heart related disease and conditions, such as ventral arrhythmias, such as tachycardias. CDC-derived exosomes delivered by endocardial injection can diminish the total amount of isolated late potentials associated with an isthmus of slow conduction, while reducing the isoelectric interval between late abnormal ventricular activity and decreasing the incidence of inducible ventricular arrhythmias, thereby providing a biological treatment for arrhythmias which otherwise requires therapeutic interventions with adverse effects.

CDC-derived exosomes for treatment of ventricular tachyarrythmias

Several embodiments disclosed herein relate generally to methods and compositions for the generation of biological pacemakers. In some embodiments, the methods comprise contacting non-pacemaker cells with one or more transcription factors (in vivo or in vitro) and inducing pacemaker functionality in the cells.

Transcription factor-based generation of pacemaker cells and methods of using same

Several embodiments relate to methods of repairing and/or regenerating damaged or diseased tissue comprising administering to the damaged or diseased tissues compositions comprising exosomes. In several embodiments, the exosomes comprise one or more microRNA that result in alterations in gene or protein expression, which in turn result in improved cell or tissue viability and/or function.

Exosomes and micro-ribonucleic acids for tissue regeneration

The present invention relates to novel compositions and methods to induce, and/of modulate bio-electrical rhythms (e.g. in cardiac, neuronal and pancreatic cells) by fine-tuning the activity of HCN-encoded pacemaker channels via a novel protein- and genetic-engineering approach to augment or attenuate the associated physiological responses (e.g. heart beat, neuronal firing, insulin secretion, etc) for achieving various therapeutic purposes (e.g. sick sinus syndrome, epilepsy, neuropathic pain, diabetes, etc).

Modulation of bio-electrical rhythms via a novel engineering approach

The present invention relates to novel compositions and methods to induce, and/or modulate bio-electrical rhythms (e.g. in cardiac, neuronal and pancreatic cells) by fine-tuning the activity of HCN-encoded pacemaker channels via a novel protein- and genetic-engineering approach to augment or attenuate the associated physiological responses (e.g. heart beat, neuronal firing, insulin secretion, etc) for achieving various therapeutic purposes (e.g. sick sinus syndrome, epilepsy, neuropathic pain, diabetes, etc).

The invention relates to secreted proteins from cardiac stem cells (cardiospheres and cardiosphere-derived cells) or myocytes for diagnostic and/or therapeutic use.

Cardiac stem cell and myocyte secreted paracrine factors

A computed tomography system has a support stage constructed and arranged to support a subject while under observation, an x-ray illumination system arranged proximate the support stage to illuminate the subject with x-rays, an x-ray detection system arranged proximate the support stage to detect x-rays after they pass through the subject and to provide signals based on the detected x-rays, and a data processing system in communication with the x-ray detection system to receive the signals from the x-ray detection system. The computed tomography system has a dynamic mode of operation and a scanning mode of operation. The data processing system extracts information concerning a dynamic process of the subject based on signals from both the dynamic mode and the scanning mode of operation.

Growing community of inventors

Lutherville, MD, United States of America

Eduardo Marban