Recent Patents on Regenerative Medicine - Volume 3, Issue 1, 2013

Regenerative medicine using pluripotent stem cells represents the future for curing developmental abnormalities, degenerative disorders and aging-related illnesses. However, today's regenerative medicine faces two major challenges with respect to stem cells: their shortage in supply and uncertain safety in clinical therapy. The recent discovery of induced pluripotent stem cells (iPS cells or iPSCs) derived from patients' somatic cells presents a possible solution for the supply shortage problem. Yet, iPSC generation with the enforced overexpression of previously defined four factors Oct4- Sox2-Klf4-c-Myc (OSKM) also causes oncogenic stimulation, which leads to potential tumorigenicity. The more recent development of miR302-mediated iPSC generation may further solve this problem since miR-302, a tiny 23-nucleotide non-coding microRNA (miRNA), is able to replace all four OSKM in mediating iPSC formation while preventing the onset of stem cell tumorigenicity. MiR-302-reprogrammed iPSCs (mirPSCs) not only possess a highly demethylated genome but also share >92% gene expression similarity with human embryonic stem cells (hESCs). Transplantation of mirPSCs into immunocompromised mice leads to the formation of relatively organized tissue cysts containing various cell types derived from all three embryonic germ layers (ectoderm, mesoderm and endoderm), providing a potential tool for regenerative medicine. Hence, this novel iPSC technology offers a simple, effective and safe method for not only reprogramming somatic cells to hESC-like pluripotent stem cells but also maintaining stem cell pluripotency in tumor-free conditions. Conceivably, mirPSCs present a more suitable choice of iPSCs based on current Food and Drug Administration (FDA) regulations. Due to the novelty of this recent technology, a majority of patent applications are still pending and are mainly led by two major research groups, Lin et al. (WJWU & LYNN Institute - 7 filings) and Yamanaka et al. (Kyoto University - 3 filings). This review will summarize all relevant patent applications and describe the mechanisms underlying this new miRNA-mediated iPSC generation technology.

Skeletal muscle is highly efficient at self-repair following injury via a complex interplay of muscle and nonmuscle cellular components, soluble growth factors, and the extracellular matrix. Under certain circumstances, such as after extensive acute tissue injury, prolonged periods of muscle disuse, and in some diseases, the regenerative capacity of muscle can be overwhelmed or impaired. Predictive muscle break down can also occur (e.g., in age-related loss of muscle mass and function, and post-operatively when procedures involve direct muscle damage, denervation or loss of blood supply), and strategies that facilitate muscle regeneration and reduce recovery time or the effects of ageing would be highly beneficial. Thus, there is a need for therapeutic approaches that promote muscle regeneration after injury, and/or to preemptively protect muscles from damage. Recent research has culminated in a range of patents that focus on the therapeutic enhancement of skeletal muscle regeneration and/or protection of existing muscle mass. This paper reviews recent research developments and therapeutically-based patents and patent applications that target epigenetic, paracrine, and signalling mechanisms underlying the normal regeneration process.

The mammalian heart has a limited capability of physiological cardiomyocyte turnover during adult life to substitute aged or damaged cells. While this regenerative mechanism has been preserved throughout mammalian evolution, it is insufficient to counteract more extensive tissue loss, which results in scar formation at the expense of cardiac function. In recent years, regenerative medicine studies investigated the efficiency of stem cells to regenerate the heart via celltherapy, while pre-conditioning the hostile environment of the injured cardiac tissue by administration of cell survival and anti-inflammatory molecules. Indeed, post-infarct combinatorial therapies using cells and factors (including growth factors, chemokines and cytokines) increased cardiac function recovery and tissue regeneration. In addition, the use of factors and molecules capable of inducing adult cardiomyocytes to re-enter cell cycle was explored to overcome the intrinsic cell cycle block or the loss of mitogenic stimuli in the postnatal heart. Nevertheless, the field has yet to solve significant obstacles including the incomplete differentiation of stem cells (with the associated danger of tumor formation) and the paucity of tissue-specific stem cells (specifically in adult/aged organs). In this review, we describe the advances in cardiac regenerative studies and the patented designs of new tools to heal an injured heart.

Healthy and active stem cells are able to differentiate into mature cells of the cardiac tissue, such as cardiomyocytes, fibroblasts and endothelial cells. Adult stem cells seem to be less responsive to stimuli of differentiation in cardiomiocytes, as compared to embrional stem cells. However, the extent of survival, proliferation, and cardiac differentiation of adult stem cells can be enhanced by physical and chemical agents. The chemical conditioning of cell plasticity can be performed on endogenous stem cells, directly into the beating heart, or in vitro, acting on stem cells prior to cardiac delivery. A major goal for Inventors has been the discovery of chemical compounds targeted for cardiac cell therapy, such as small-molecules that can modify the expression of hallmarks genes leading to stem cell commitment to a cardiac fate. Our review will highlight the most recent patents declaring the design of innovative chemical inducers of stem cell-derived cardiac cells.

In recent years, the concept of preserving and/or replenishing the functional β-cell mass vital to sustain insulin output and normalized blood glucose levels has gained much interest as a therapeutic approach in regenerative medicine for the treatment of Diabetes Mellitus. Herein, we surveyed the diabetes area patent literature published in recent years to identify novel uprising therapeutic targets specifically implicated in regeneration and survival. One hundred and sixty nine international patent applications filed under the Patent Cooperation Treaty (PCT) (hereinafter, patents or applications) were highlighted from which 8 particular targets stood out with more than 4 patents published within the last few years. Not surprisingly, GLP-1 analogues and DPP-4 inhibitors along with GPR119 agonists and SGLT2 inhibitors were among the top ranked candidates. However, new emerging targets into the field of regenerative medicine for the treatment of diabetes include: 1) BACE-2; a protease that was recently shown to cleave the plasma membrane glycoprotein TMEM27 (also called collectrin) resulting in the inhibition of pancreatic β cell proliferation and insulin secretion, 2) GIP; a 42 amino acid incretin hormone that potentiates glucose induce insulin secretion and protect β-cells against cytokinemediated apoptosis, 3) neurturin; a neurotrophic factor capable of improving blood glucose levels in high fat diet treated animals, and 4) LRH-1, an orphan nuclear receptor that improves islet viability. These novel targets along with GPR119 are further discussed in this review.

Stem and progenitor cells have generated considerable scientific and commercial interest in recent years due to their potential for novel cell therapy for a variety of medical conditions. A highly active research area in the field of regenerative medicine is vascular biology. Blood vessel repair and angiogenesis are key processes with endothelial progenitor cells (EPCs) playing a central role. Clinical trials for ischemic conditions, such as myocardial infarction and peripheral arterial disease, have suggested cell therapies to be feasible, safe, and potentially beneficial. Development of efficient methodologies to deliver EPC-based cytotherapies offers new hope for millions of patients with ischemic conditions. Evidence indicates that EPCs, depending on the subtype, mediate angiogenesis through different mechanisms. Differentiation into endothelium and complete integration into damaged vasculature was the first EPC mechanism to be proposed. However, many studies have demonstrated that vasoregulatory paracrine factor secretion by transplanted cells is also important. Many EPC subsets enhance angiogenesis and promote tissue repair by cytokine release without incorporating into the damaged vasculature. Whatever the mechanism, vascular repair and therapeutic angiogenesis using EPCs represent a realistic treatment option and also provides many commercialization opportunities. This review discusses recent advances in the EPC field whilst recounting relevant patents.

The information on relationships between paracrine communication and stem cells is spread over a large amount of patent and scientific publications. This article provides an overview of some major issues to be considered when searching for such information by using freely available databases. Major trends that drive innovation in scientific and patent production, as well as association between specific topics, can be established by including specific database indexing, such as MeSH and European (ECLA) and International (IPC) patent classification codes, in the search strategy. The interest in applying similar approaches for retrieving relevant information and documents is shown by some examples of quantitative and qualitative analysis of scientific and patent production related to stem cells in general, and on the effect of paracrine factors on the isolation, differentiation, or use of stem cells in particular.

The recent patents annotated in this section have been selected from various patent databases, and are relevant to the articles published in this journal issue. The patents are categorized in fast emerging areas of regenerative medicine e.g. stem cells, human embryonic stem, gene therapy, tissue engineering, regenerative biomolecules, use of biomaterials for treating disease and injury, and tissue/ organ regeneration related to regenerative medicine.