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June 15, 2017 (Vol. 37, No. 12)

Targeting Progenitor Cells to Regenerate Damaged Tissue

Progenitor Cells Studies May Show the Path toward Curing Chronic Diseases

  • Exosomes for Muscle Regeneration

    Capricor Therapeutics President and CEO Linda Marbán, Ph.D., describes the company’s regenerative medicine approach succinctly: “We take cardiospheres and turn them into cardiosphere-derived cells (CDC), a progenitor cell which can function as a local drug-delivery system.”

    After the discovery of these cardiac-derived cells, the researchers found that they released growth factors, such as IGF-1, FGF, and VEGF, and when delivered systemically, these cells would travel to the site of tissue injury (i.e. to the heart in the case of myocardial infarction). While they persisted at the site of injury for a relatively short time, about a month, the benefits they delivered continued for many months. Capricor developed a method for producing allogeneic cardiosphere-derived cells from donor hearts and began testing the safety and efficacy of its CAP-1002 off-the-shelf product.

    The “drugs” these cells are delivering are exosomes, says Dr. Marbán, “nanometer-size lipid bilayer vesicles packed with RNAs and some proteins that epigenetically modify cellular proteins such that they can change the behavior of a cell.” Capricor is developing the exosomes as a separate, second product pipeline.

    When released by the CDCs, the exosomes are quickly taken up by neighboring cells. The results suggest that the exosomes are “epigenetically modifying protein expression, not changing the genes themselves, and in that way changing the behavior of the cells that are endogenous to the space,” Dr. Marbán says. “We also think the cells themselves put out an alarm bell for natural stem cells to arrive on the scene and repair tissue.”

    Early clinical results with CAP-1002 from the CADUCEUS trial in patients who experienced a massive heart attack showed a significant reduction in scar size and significant increases in muscle mass at the affected area, which lasted at least a year after a single administration of CAP-1002. However, a recent interim analysis of data from the Phase II ALLSTAR trial in adults who experienced a massive heart attack showed that treatment with CAP-1002 was unlikely to achieve the primary efficacy endpoint of change in infarct size.

    These results have led Capricor to focus its resources on its other ongoing clinical development program for CAP-1002, as a treatment for patients with DMD. The company recently released six-month results from the 25-patient randomized Phase I/II HOPE trial in young males with DMD with advanced cardiac disease. The results showed significant improvement in some measures of cardiac and upper-limb function compared to usual care. Capricor hopes to initiate a repeat-dose clinical trial of intravenous CAP-1002 in DMD in the second half of 2017 that would primarily evaluate the effects of treatment on skeletal (noncardiac) muscle function.

  • Regenerating the Body with Drugs

    Essential parts of the human body’s regeneration machinery are adult stem cells (or progenitor cells) that reside in our tissues and are capable of differentiating into replacement cells that maintain organ function following disease or injury. The molecular pathways that cause tissue repair or regeneration can be complex and few are well understood.

    However, there are well-known examples of simple biochemical stimuli that regenerate specific tissues. Perhaps the best is erythropoietin (EPO), a growth factor produced by oxygen-sensitive cells in the kidney, which stimulates hematopoietic erythroid progenitor cells to differentiate into red blood cells. A related growth factor, thrombopoietin (TPO), signals myeloid progenitor cells to differentiate into platelets that produce platelets, essential for blood clotting. Both EPO and TPO are natural growth factors that can be used clinically to regenerate specific cell types.

    While EPO became the first blockbuster recombinant biologic drug, TPO was superseded in development by a synthetic chemical mimetic (Promacta®, GSK) that is orally available and less immunogenic. Promacta showed that a small-molecule drug can be used to
    regenerate tissues of the body. What is the prospect, therefore, to develop such drugs further?

    “High-content screening of human progenitor cells can be used to discover compounds that stimulate differentiation to specific cell types required to regenerate ailing organs,” says Yen Choo, Ph.D., founder and executive chairman of Plasticell and founder and CEO of Progenitor Therapeutics. While cell-based screening has multiple advantages in drug discovery, many of the progenitor cells of interest are relatively rare, or difficult to isolate, or both.”

    According to Dr. Choo, companies like Progenitor generate rare progenitor cells for screening using more abundant pluripotent cells (e.g., human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC) as starting material. “

    “This strategy has been used to create and screen high quality human progenitors from cartilage, myelin, and muscle—and regenerative drugs have been discovered to treat indications such as osteoarthritis, multiple sclerosis and muscular dystrophies,” added Dr. Choo.

  • Cancer Drug Holds Promise for Treating Allergies

    Researchers at the Northwestern University Feinberg School of Medicine have found that a drug typically used to treat certain types of leukemia and lymphoma can also prevent reactions to some of the most common allergic reactions. Findings from the new study—published recently in the Journal of Allergy and Clinical Immunology in an article entitled “Ibrutinib, a Bruton’s Tyrosine Kinase Inhibitor Used for Treatment of Lymphoproliferative Disorders, Eliminates Both Aeroallergen Skin Test and Basophil Activation Test Reactivity”—could also have even greater implications for adults with food allergies.

    The scientists discovered that cancer patients who were allergic to allergens such as cat dander and ragweed saw their allergic skin test reactivity reduced by 80% to 90% in 1 week, and this persisted with continued use of the drug for at least 1 to 2 months.  

    “It almost completely knocked out the patients’ skin test and blood cell allergic reactivity,” remarked senior study investigator Bruce Bochner, M.D., professor of medicine at Northwestern University Feinberg School of Medicine.

    In the current study, Dr. Bochner and his colleagues performed traditional allergy skin tests and the basophil activation test, a related allergy test using blood cells, on cancer patients before they had taken the drug ibrutinib, 1 week after use, and again after 1 to 2 months of continued use. Ibrutinib is an FDA-approved drug currently approved as a successful and less toxic alternative to chemotherapy for patients with chronic lymphocytic leukemia and mantle cell lymphoma.  

    Previous research on ibrutinib told the researchers that the compound was a generally well-tolerated cancer drug successful in blocking a protein within cells called Bruton’s tyrosine kinase (BTK). BTK plays a crucial role in B-cell activation, growth, and maturation and mast cell and basophil activation, the latter two cells being responsible for immediate allergic reactions. The investigators focused on whether this BTK inhibitor could also shut down an enzyme inside cells that is involved when you have an allergic reaction.

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