Smooth muscle cell plasticity is considered a prerequisite for atherosclerosis and restenosis following angioplasty and bypass surgery.
Patients with primary biliary cirrhosis are well known for the presence of titer antibodies against dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex. We have taken advantage of a cDNA probe for dihydrolipoamide acetyltransferase to explore the possibility of polymorphism of the E2 subunit by probing genomic DNA from 38 patients with primary biliary cirrhosis and 26 healthy controls. To detect restriction fragment length polymorphism, DNA was digested with ten specific restriction enzymes that often detect polymorphism, including Bam HI, Bgl II, Eco RI, Hind III, Hinf I, Msp I, Pst I, Pvu II, Rsa I and Taq I. A Taq I polymorphism was found in 19 of 38 patients with PBC and 6 of 26 normal controls. In addition, using fluorescence in situ hybridization, the gene for dihydrolipoamide acetyltransferase was mapped on human chromosome 11 band q23.1. Interestingly, this region of the long arm of chromosome 11 is often associated with cytogenetic abnormalities, including translocations.
Interleukin-2 (IL-2) and interleukin-15 (IL-15) promote anti-tumor immune activity by stimulating effector T and NK cells expressing the β and γ subunits of the IL-2 and IL-15 receptors. However, preferential activation of off-target cell populations expressing the high-affinity α subunit (including regulatory T cells, eosinophils, and endothelial cells) has limited the safety, therapeutic benefit, and widespread clinical use of these cytokines. Recently, we used sophisticated computational methods to create Neoleukin-2/15 (Neo-2/15), an entirely de novo α-independent agonist of both the IL-2 and IL-15 receptors. Unlike strategies that attempt to sterically inhibit or mutate the α-binding region of IL-2 or IL-15, Neo-2/15 was computationally designed to have no α-binding interface, while also having increased affinity for the β and γ signaling subunits. As a result, Neo-2/15 stimulates effector T and NK cells more potently and selectively than IL-2 or IL-15. Here, we report on the preclinical development and pharmacology of NL-201, a long-circulating variant of Neo-2/15 that is intended for clinical applications. NL-201 was derived from Neo-2/15 via the site-specific conjugation of a single PEG molecule and is manufactured using a simple and scalable process. NL-201 has a prolonged blood half-life and a sustained pharmacodynamic effect while retaining the high potency, selectivity, and thermodynamic stability of Neo-2/15. Preclinical studies demonstrate the robust antitumor activity of NL-201 as a single agent across a wide range of syngeneic murine tumor models, including those that do not respond well to checkpoint inhibitors. Due to its stability, high potency, and selectivity, NL-201 may overcome the long-standing challenges associated with the clinical use of IL-2 and IL-15 for cancer immunotherapy. Citation Format: Carl D. Walkey, Paul Hara, Laurie Tatalick, Umut Ulge, Jonathan Drachman, Daniel-Adriano Silva. Pre-clinical development of NL-201: A de novo α-independent IL-2/IL-15 agonist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4518.
High transduction frequency of hematopoietic stem/progenitor cells is essential to derive clinical benefits for treating certain inherited and acquired diseases. We demonstrate here stable gene transfer into human bone marrow-derived CD34+ progenitors using cationic lipids to facilitate GaLV and amphotroic pseudotyped retroviral-mediated transductions. Furthermore, the transgene was detected only in the progeny of flow cytometer sorted CD34+ population transduced by the LAPSN (PG13) viral vector in the presence of cationic lipids but not when transduction was facilitated with conventional polycations Polybrene or protamine sulfate. Thus, a combination of GaLV pseudotyped vectors and cationic lipids results in increased transduction frequencies of the CD34+ cells without a requirement of extended in vitro culture, or co-cultivation with producer cell lines. These improvements may result in the production of therapeutically significant quantities of genetically modified hematopoietic cells.
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