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Feature Articles: 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

  • The promise of cell therapy for regenerative medicine is often viewed as being synonymous with stem cell therapy, but some companies are instead successfully bringing progenitor cell-based cell therapy approaches through preclinical and clinical development. They are targeting disorders that include type 1 diabetes, hearing loss, Duchenne muscular dystrophy (DMD), osteoarthritis, and multiple sclerosis, for example.

    Innovative strategies that aim to deliver progenitor cells to patients may then rely on the cells’ ability to differentiate into healthy adult cells to restore missing tissue and function, or they may utilize the progenitor cells as vehicles for delivering growth factors and other signals to regenerate damaged tissue. Yet other novel approaches seek to identify small-molecule drugs that can stimulate the regenerative capabilities of progenitor cells that are already present in the body.

  • Seeking a Cure for Diabetes

    Type 1 diabetes (T1D) is the primary therapeutic focus of the stem cell-derived cell replacement therapies being refined by ViaCyte. The company has developed and standardized a manufacturing process that involves directed differentiation of embryonic stem cells to produce pancreatic progenitor cells, a product that it calls PEC-01™. When implanted subcutaneously, PEC-01 cells mature into pancreatic endocrine cells. They are able to form all five hormonal subtypes of pancreatic islet cells, including the insulin-producing beta cells and glucagon-producing alpha cells.

    ViaCyte’s islet replacement therapy “has the potential to provide a functional cure for T1D as well as a treatment for patients with insulin-dependent type 2 diabetes,” says company President and CEO Paul Laikind, Ph.D. Unlike implanted cadaver-sourced islet cells, which have allowed some individuals with diabetes to live without the need for exogenous insulin for many years, “our approach provides an unlimited supply of cell material,” he adds.

    ViaCyte is developing two PEC-01-based products. PEC-Encap™ fully encapsulates the progenitor cells in the retrievable Encaptra® cell delivery system that is designed to protect the cells from exposure to the patient’s immune system. With the PEC-Direct product, the cells are delivered in a device containing engineered pores that allow for direct vascularization and more robust engraftment. The cells in PEC-Direct are not protected from the immune system, and treated patients require immunosuppression.

    PEC-Direct is targeted for use in patients with T1D who are at high risk for acute complications, such as hypoglycemia-unaware patients. ViaCyte will soon begin enrolling patients in the first phase I/II trial of PEC-Direct. “Over the next 12–18 months, we hope to show both proof-of-mechanism—that the cells are engrafting and differentiating as expected—and proof-of-efficacy, which will be insulin production, as measured by C peptide production and other endpoints such as reduced insulin utilization,” Dr. Laikind tells GEN.

    Initial testing of PEC-Encap at subtherapeutic doses, in 19 patients in a STEP ONE trial, demonstrated the safety of the product and approach. “We put in ‘sentinels,’ small devices with small amounts of cells that we could withdraw periodically and do histology on to understand how the cells were faring in a patient,” says Kevin D’Amour, Ph.D., vice president of research and CSO of ViaCyte.

    In addition to seeing no evidence of autoimmune or allogeneic rejection of the cells, the results showed vascularization, engraftment, and survival of the cells for at least three months, with differentiation into islet subtypes. Despite these encouraging findings, “engraftment was challenging and not consistent,” says Dr. D’Amour, and ViaCyte is working with materials science company W.L. Gore & Associates to improve the implantable device used to deliver PEC-01 cells and achieve better engraftment for PEC-Encap, which is targeted for use in all patients with T1D.

  • Restoring Hearing

    At Frequency Therapeutics, instead of starting with stem cells that have to differentiate or trying to deliver progenitor cells to a patient, the researchers are developing small-molecule therapeutics that can stimulate dormant progenitor cells already present “right where the body needs them,” says Chris Loose, Ph.D., co-founder and CSO of Frequency. The targeted progenitor cells, located in the inner ear in the case of Frequency’s lead regenerative medicine product, are “predestined to know how to make a certain kind of cell”—a functional hair cell with the capability to restore hearing in people with chronic hearing loss.

    The work at Frequency builds upon the research of Robert Langer, Sc.D., and Jeff Karp, Ph.D., at MIT and Harvard Medical School on the Lgr5+ progenitor cell, first discovered in the epithelium of the gastrointestinal tract: a highly regenerative tissue, then shown to be present, but dormant, in the inner ear and the source of the cochlear hair cells essential for hearing.

    Early on, the Frequency team considered the advantages of targeting the progenitors. One could stimulate them to become a little more stem-like and send them into their normal pathway [of asymmetric division], where they replace themselves and form the cell of interest . . . in this case, a hair cell. “Once you wake them up,” notes Dr. Loose, “they can follow much of the rest of the path on their own.” This thinking led to the progenitor cell activation (PCA™) platform, which Frequency describes as a controlled approach to activating “stemness” to stimulate Lgr5+ progenitor cells to divide and differentiate.

    Unlike a genetic approach, which might turn these pathways on constitutively, using small molecules to achieve transient stimulation, so the progenitor cells divide, allows the effect to be “turned off” once the drugs are removed; but once formed, the hair cells could last a person’s lifetime. “There are no permanent genetic changes, which contribute to the safety of this approach,” Dr. Loose adds. Frequency delivers its drug via injection directly into the middle ear.

    A recent article in Cell Reports (McLean et al. 2017;18[8]:1917–1929) demonstrates a  <2,000-fold expansion of Lgr5+ cells following small-molecule treatment and the formation of more than 11,500 hair cells from a single mouse cochlea, compared with less than 200 without treatment.

    “We expect to be in the clinic within the next 12 months,” says David Lucchino, CEO. Frequency recently received $32 million in series A financing to support its clinical development program.

  • Stimulating Progenitor Cells

    Plasticell, a developer of cell therapies including hematopoietic cell-replacement therapies, recently announced a collaboration with Kings College London to initiate preclinical trials of its artificial blood platelet product, manufactured from pluripotent stem cells. Plasticell has also received funding from Innovate UK to support a £1.1-million project to manufacture red blood cells from pluripotent stem cells. The company uses its proprietary CombiCult® bead-based combinatorial screening technology to facilitate high-throughput differentiation of stem cells—human embryonic or induced pluripotent stem cells—into specific cell lineages.

    Progenitor Therapeutics, a spinout of Plasticell, applies the CombiCult technology to generate progenitor cells,—which are usually present in very small numbers in the body,—which it then uses in its ProScreen™ drug-screening platform. In contrast to Plasticell’s cell-therapy approach to regenerative medicine, Progenitor’s goal is to identify small-molecule drugs that can stimulate progenitor cells to regenerate targeted tissues damaged by injury, disease, or aging. Progenitor is partnering with GlaxoSmithKline to screen GSK’s compound libraries. Initial therapeutic targets include osteoarthritis, multiple sclerosis, and muscular dystrophy.

    “We have been identifying a lot of drug assets suitable for repurposing,” says Yen Choo, Ph.D., CEO of Plasticell and Progenitor Therapeutics.

    Dr. Choo credits the GSK collaboration to the company’s proof-of-concept data in creating myeloid progenitors, the precursors to megakaryocytes and platelets, in sufficient quantity and purity to use in high-throughput drug screening to re-discover Promacta, GSK’s small-molecular regenerative drug that acts on the TPO receptor. The company has identified regenerative drug candidates for stimulating cartilage production that are ready to take into animal testing. The company’s program in multiple sclerosis targets oligodendrocyte progenitor cells in multiple sclerosis lesions to stimulate remyelination. Small molecules that can act on muscle progenitor cells are the focus of screening campaigns to identify drug candidates for muscle regeneration in DMD and post-surgical repair.