Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 4, Issue 2, 2010

Serum amyloid A (SAA) and its protein family are highly conserved acute phase proteins elevated to high levels during acute inflammation. Among the many different roles SAA plays, one of the major ones is believed to be the regulation of mechanisms designed to fight injuries, heal infections and bring about their resolution to homeostasis. In the circulation, SAA is mainly associated with high density lipoproteins, can influence cholesterol transport and has been implicated in the pathogenesis of atherosclerosis, rheumatoid arthritis, and cancer. The deposition of SAA cleavage products can lead to amyloidosis. So, patents describing possible modifications of SAA pathophysiological role/s are relevant. SAA is one of the highest positively responsive acute phase proteins in humans, as well as in animals, and its levels have been used to monitor diseases, treatment strategies and predict outcomes. The major aims of this overview were to determine the potential for SAA as a diagnostic tool (in terms of SAA secretion as a cause or consequence of disease) and to critically analyse patents proposing SAA measurement methodologies, in order to determine the most optimal. A compilement of SAA patents predominantly generated within the past decade will also enable a better understanding of SAA, its genetics, the expression of its isoforms, associations with other proteins, especially its receptors, which could be important in diagnosis and/or treatment of chronic inflammatory diseases.

The naturally arising FoxP3+ CD4 T (nTr) cells are absolutely required for the induction and maintenance of immunological tolerance to self antigens. In addition to their physiological role, nTr cells can also be utilized effectively for treatment of autoimmune diseases, allograft rejection and graft versus host disease in animal models. Due to the very low frequency in the peripheral blood, nTr cells need to be expanded in ex vivo to generate sufficient numbers for therapeutic applications. The nTr cells can be expanded either polyclonally using anti-CD3/CD28 antibodies, or in an alloantigen-specific manner using allogeneic antigen presenting cells. The allospecific nTr cells are more therapeutically effective with less risk to cause non-specific immune suppression as compared to polyclonal nTr cells. Despite the success in expanding murine nTr cells, little success has been achieved in expanding human allospecific nTr cells, posing a major barrier to the development of nTr cell-based immunotherapy in humans. We have found that mouse B cells preferentially activate and induce expansion of nTr cells in allogeneic mixed lymphocyte reactions. The preferential expansion of Foxp3+ T cells can be further enhanced by a partial blockade of class II MHC-TCR interaction, suggesting that nTr cells preferentially respond to weak TCR stimulation. Extending the findings with murine B cells, we have further found that human B cells can efficiently expand allogeneic human nTr cells ex vivo. The expanded nTr cells express very high levels of FoxP3, maintain an anergic phenotype, and are potent suppressor cells capable of inhibiting the alloreactivity of thirdparty responder T cells at very low nTr-to-T effector cell ratios in an alloantigen-specific manner. The allospecificity possessed by the B cell-expanded nTr cells is not determined by the HLA haplotypes of the nTr cells, but it is induced and determined by the HLA haplotype of the B cells used to expand nTr cells. Our findings represent a significant advance in the development of nTr cell-based immunotherapy in humans and raise the possibility of using “off-the-shelf” third-party nTr cells for therapeutic applications. This review also outlines some patents on immunotherapy.

Inborn errors of metabolism (IEM) is a group of around 500 diseases, characterized by function alteration in proteins or enzymes involving the intermediary metabolism of carbohydrates, amino acids, and lipids, among others. Since their discovery at the beginning of the last century, IEM have made important contributions to different fields of biochemistry and medicine. In this paper, a review of the recent patents for the diagnosis and treatment of IEM will be presented. During the last years significant achievements have been done for their diagnosis, including the use of tandem mass spectrometry for the identification of an important number of disorders and the use of genetic and immunological techniques, which have allowed the development of reliable diagnosis tests. Also, important progresses has been done in therapeutic strategies, most of them based on the use of recombinant DNA technology, such as enzyme and gene therapies, and the use of small molecules for chaperone and substrate reduction therapies. Improvements in classical treatments, like nutritional management, have also contributed in the generation of new therapeutic strategies for these patients.

Dolichol is a polysoprenoid lipid ubiquitous in eukaryotic cell membranes. Its molecular structure comprises a sequence of E and Z unsatured isoprene units tethered by a satured isoprene unit bearing a hydroxyl group. Dolichol is mostly present in the native form or esterified by lipid acids, and it is thought to locate in the innermost part of the membrane double layer, intertwining with the hydrophobic terminus of the phospholipids. In spite of this peculiar arrangement, no clear biological function of dolichol has been evidenced yet, although a minor dolichyl phosphate pool is known to assist the N-glycosylation of proteins in the endoplasmic reticulum. Dolichol was recently found to strongly interact with free-radicals, leading to a fast molecular disruption without peroxidized by-products. This scavenging property may explain why dolichol accumulates with age, representing an excellent biomarker of the ageing process also sensitive to ageing-preventing dietary regimes in living animals. Furthermore, dolichol was shown to possess photoprotective characteristics towards UV radiation. On account of its high biocompatibility, its free-radical scavenging and photoprotective properties, and its easy preparation from vegetable extracts, dolichol has been proposed as main components for dermatological and cosmetic compositions. The scientific background and the related patents are reviewed here.

The asymptomatic primary hyperparathyroidism (PHPT) is one of the most common endocrinopathies. Considering relatively slow progression of the disease, the untreated PHPT patients are still at risk of classical (particularly osteoporosis) and non-classical (cardiovascular, neurocognitive and psychosocial) complications. The careful evaluation of subjects, including exclusion of the secondary hyperparathyroidism, is necessary, as some of the patients are normocalcemic even in the presence of the disease complications. There are no established risk factors for developing symptomatic disease. At the moment surgery, particularly minimally invasive procedures, seems the most beneficial and cost-effective therapy for asymptomatic PHPT. According to the 2008 International Workshop guidelines at least part of the patients may be followed-up conservatively, provided that they will be closely monitored for possible progressive disease. Pharmacological approach seems to be an option for such patients. The anti-resorptive therapies, particularly biphosphonates, are effective in management of PHPT-related osteoporosis. Calcimimetics are very promising agents lowering calcium and PTH levels, however costs of the treatment may limit their long-term use in asymptomatic PHPT. Also adequate Vitamin D nutrition is essential for conservative management of such patients. This article outlines different methods and recent patents for the treatment of hyperparathyroidism.

Dendritic cells (DCs) are a vital component of the immune system. Their main function is to detect the presence of pathogens and act as antigen presenting cells, processing antigenic material then presenting it on their surface in the context of major histocompatibility complex (MHC) molecules to lymphocytes. Thus DCs provide a crucial link between innate and adaptive immunity. DCs efficiently activate naive T cells making it particularly important that they are correctly targeted by vaccines in order to induce both effector and memory responses. This property of DCs has important clinical application in the development of cancer vaccines. However, under certain circumstances DCs can also tolerize T cells, exploiting this may lead to the development of novel therapies for T-cell mediated autoimmune diseases. Recently, there has been substantial progress in the understanding of how to manipulate DCs, however the challenge of translating this from experimental models into the clinic remains. Some patents on DCs, which may lead to the development of effective immunotherapy, are discussed in this review.

In spite of optimal treatment of LDL - cholesterol, as per evidence -based guidelines, only a one third reduction in cardiovascular risk is achieved in our patients. This has led to the realization that other types of cholesterol, too, need to be treated, in order to achieve ideal cardiovascular health. The review focuses on high density lipoprotein (HDL) cholesterol as a target for treatment, its importance, relevant patents and current as well as future treatments.

An enzymatic posttranslational modification of proteins at serine or threonine residue by β-N-acetyl glucosamine (GlcNAcylation, also known as O-GlcNAc modification), a product of hexosamine biosynthetic pathway (HBP), has been emerging as a fundamental regulatory mechanism like protein phosphorylation. A significant surge in the information in recent years due to technological advancement has implicated an important role for GlcNAcylation in a wide variety of cellular processes including cell division, metabolism, signal transduction and transcription. Furthermore, GlcNAcylation in proteins has been found to be intimately associated with phosphorylation which is one of the most diverse regulatory mechanisms in the biological system. Therefore, it is likely that altered protein GlcNAcylation may underlie etiology of various diseases including type 2 diabetes. Emerging evidence strongly indicates a role for GlcNAcylation in the development of insulin resistance, a hallmark of type 2 diabetes. Recent findings on protein GlcNAcylation, especially in relation to insulin signaling and insulin resistance have regenerated an immense interest in this field; which was first reported in early nineties. Here we summarize recent development in this area along with unanswered questions and future direction at the end. Some of the recently patented technologies in relation to GlcNAcylation are also summarized in this review. Further investigations in this area are timely and of critical importance with continuous increase in the incidence of type 2 diabetes and diabetes associated complications worldwide. A better understanding of the underlying mechanisms may provide new opportunities for the prevention and treatment of type 2 diabetes.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets & therapeutic agents related to endocrine, metabolic and immune drug discovery.