Recent Patents on Regenerative Medicine - Volume 1, Issue 3, 2011

In recent years, important advances were made to clarify the biology and potential use of mesenchymal stem cells (MSC) in the therapy of a number of disorders. MSC are present in a number of tissues, ranging from adult bone marrow, to several adult organs, adipose tissue and, in the last years, the fetal-associated (also named as extraembryonic) tissues (e.g. placenta, amniotic membrane, umbilical cord). In particular, research on cells derived from mature umbilical cord, a tissue which is still discarded at birth, showed that mesenchymal stem cells can be successfully isolated from the Wharton's jelly (WJ), the main constituent of this organ. This review will take in to account the patents which were developed concerning the isolation procedures of cells from WJ (both using enzymatic or enzyme-free techniques), the development of differentiation protocols and the in vivo applications in cellular therapy approaches using both differentiated and undifferentiated cells. In addition, we will focus on the latest advances on the biology of these cells, in particular for what concerns their hypoimmunogenicity in in vitro and in vivo, and their potential application as immunomodulatory cells besides their differentiation capacity.

Recent observations that human mesenchymal stromal cells (MSCs) are non-immunogenic and possess the capacity to modulate the responses of immune cells has caused a fundamental paradigm shift in exploiting the therapeutic potential of MSCs. While MSCs are still being considered for regenerative purposes, particularly for musculoskeletal diseases, their role in treating inflammatory conditions, wound healing and immune diseases is receiving more and more attention. Studies in animal models using human MSCs have been encouraging. However, clinical results using MSCs for treatment of autoimmune diseases including Crohn's Disease, Systemic Lupus Erythematosus and Multiple Sclerosis have been mixed. Conflicting results have also been obtained in using allogeneic MSCs to treat acute, steroid-refractory graftversus- host disease (GvHD). This review examines the different clinical results and cites mechanistic in vitro and preclinical studies to provide some insight into these results. Recent patents and applications pertaining to the use of MSCs from various sources for treating autoimmune and inflammatory diseases and disorders, and technologies to enhance or suppress this immune modulation are also discussed.

Acute and chronic heart failure and complex congenital heart disease result in inadequate cardiac output for which in vitro tissue engineering of implantable, functional cardiac tissue is an attractive alternative to heart transplantation, the gold-standard therapeutic modality which is severely limited by a donor organ shortage. A variety of strategies to generate, optimize, vascularize and implement engineered heart tissue (EHT) have been proposed and evaluated. Here, we review the patented methods of various research groups and investigators to generate EHT as well as recent advances in the development of vascularized and human EHT.

Pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, hold great promise as a cell source for regenerative therapies to treat many major diseases characterized by an irreversible loss of functional tissues. However, the future clinical application of pluripotent stem cells faces a number of obstacles regarding the safety, efficiency and long-term benefits. Some of these challenges are being addressed by the chemical biology approach using small molecules. In this paper, we review the recent progress and patents on small molecules which promote pluripotent stem cell maintenance, reprogramming, and direct differentiation with a focus on cardiomyogenesis.

Collagen is the most abundant protein in mammals and comprises about ninety percent of connective tissue. Thus, defective collagen can cause many health problems, particularly in the musculoskeletal system, including degenerative joint disease, degenerative spinal disc disorder, disc herniations, tendonitis/osis, osteoporosis, sprains and strains, etc. These pathological conditions, plus the fact that the tensile strength of tissues is essentially provided by collagen, have made defects in collagen per se and collagen-based tissues primary targets for developing regenerative medicine strategies. Consequently, collagen and collagen-like materials have emerged as major substrates for tissue and/or chemical engineering. Traditionally, collagen has been isolated in soluble format from animal tissue and reconstituted into molded sponges or hydrogels. More recent techniques have employed the controlled deposition of nanofibers via electrospinning. However, the use of cells to deposit their own collagenous matrix is receiving increased attention, especially given the potential for autologous treatment and more physiological structural configurations. The recent popularization of detergentbased “decellularization” of complete tissues/organs, which leaves behind a collagen-containing extracellular matrix that was secreted by the original resident cells, opens the possibility that cells themselves could be used to better generate or modulate physiological collagenous matrices. Therefore, this review will focus on recent patents related to the use of donor cells to realize collagen synthesis, enrichment, and repair, with the goal of clinical application.

Myostatin is a major negative regulator of muscle mass. Interestingly, myostatin can modulate the expression and functional activity of myogenic regulatory factors such as MyoD and Forkhead BoxO (FOXO). Recently, Akt, a crucial enhancer of muscle hypertrophy, has been shown to interact with Smad2 and 3, downstream of a myostatin-dependent pathway. Ubiquitin-proteasome signaling is the most common system of protein degradation during rapid musclular atrophy after denervation, immobilization, or hindlimb suspension (unweighting) through the downstream mediator Atrogin-1 and FOXO. Deregulation of myostatin signaling has been implicated in the pathology of a number of major muscle wasting disorders including several muscular dystrophy, sarcopenia, cachexia, and amyotrophic lateral sclerosis. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting muscle wasting, in particular, myostatin and proteasome-inhibitors. This patent review provides an overview of recent attempts to attenuate or inhibit muscle wasting using new and improved myostatin- and proteasome-linked agents. Proteasome inhibitor may not be appropriate for blocking muscle atrophy induced by sarcopenia and cachexia.

Liver failure remains one of the major causes of morbidity and mortality in the world. All published studies about stem cell therapy at present are limited by small patient numbers and by the design as pilot safety and feasibility studies. Various experimental studies provided evidence that the infusion or injection of stem or progenitor cells may reduce liver fibrosis. Moreover, predominantly bone marrow-derived cells were shown to augment liver function, thereby providing a novel therapeutic option for the treatment of liver failure. This article summarizes the current experimental and clinical evidence for a potential role for stem cells in liver regeneration. Special attention will be given to patents with focus on use of stem cells in chronic liver disease models. Many questions still need to be answered, such as what the current status are of phases I, II, III studies regarding stem cell therapy. We describe the best available evidence from systematic reviews, randomized controlled studies and observational studies where appropriate. Data from literatures suggest that in chronic liver diseases, the future of stem cell therapy is still uncertain. Special attention will be given to patents with focus on use of stem cells in chronic liver disease models. Many technical questions have yet to be answered before stem cell therapy can be applied to its fullest potential in the clinic.

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....