TY - JOUR T1 - Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease. JF - Biomaterials Y1 - 2022 A1 - Kotla, Niranjan G A1 - Singh, Rajbir A1 - Baby, Becca V A1 - Rasala, Swetha A1 - Rasool, Jawad A1 - Hynes, Sean O A1 - Martin, Darrell A1 - Egan, Laurence J A1 - Vemula, Praveen K A1 - Jala, Venkatakrishna R A1 - Rochev, Yury A1 - Pandit, Abhay AB -

Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn's and ulcerative colitis, is highly challenging. Recent advances in colitis therapy medications are expanding opportunities for improving local on-site drug availability by minimising the associated systemic side-effects. Drug delivery with targeted carrier systems has shown the potential to increase site-specificity, stability, and therapeutic efficacy. Herein, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. This system showed preferential adhesion on a charge-modified surface in vitro, and in both dextran sulfate sodium (DSS) and TNBS colitis mice in vivo models. IT-NCs showed improved colitis phenotype therapeutic efficacy in both animal models compared to free drug. Furthermore, ex vivo study of colon tissue biopsies from patients with colitis revealed that IT-NCs adhered preferentially to inflamed biopsies compared to normal. Together, our results suggest that IT-NCs have promising therapeutic potential as delivery carriers' in colitis management.

VL - 281 ER - TY - JOUR T1 - Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. JF - NPJ Genom Med Y1 - 2022 A1 - Lesurf, Robert A1 - Said, Abdelrahman A1 - Akinrinade, Oyediran A1 - Breckpot, Jeroen A1 - Delfosse, Kathleen A1 - Liu, Ting A1 - Yao, Roderick A1 - Persad, Gabrielle A1 - McKenna, Fintan A1 - Noche, Ramil R A1 - Oliveros, Winona A1 - Mattioli, Kaia A1 - Shah, Shreya A1 - Miron, Anastasia A1 - Yang, Qian A1 - Meng, Guoliang A1 - Yue, Michelle Chan Seng A1 - Sung, Wilson W L A1 - Thiruvahindrapuram, Bhooma A1 - Lougheed, Jane A1 - Oechslin, Erwin A1 - Mondal, Tapas A1 - Bergin, Lynn A1 - Smythe, John A1 - Jayappa, Shashank A1 - Rao, Vinay J A1 - Shenthar, Jayaprakash A1 - Dhandapany, Perundurai S A1 - Semsarian, Christopher A1 - Weintraub, Robert G A1 - Bagnall, Richard D A1 - Ingles, Jodie A1 - Melé, Marta A1 - Maass, Philipp G A1 - Ellis, James A1 - Scherer, Stephen W A1 - Mital, Seema AB -

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

VL - 7 IS - 1 ER - TY - JOUR T1 - Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival. JF - Cancers (Basel) Y1 - 2021 A1 - Zaarour, Rania F A1 - Azakir, Bilal A1 - Hajam, Edries Y A1 - Nawafleh, Husam A1 - Zeinelabdin, Nagwa A A1 - Engelsen, Agnete S T A1 - Thiery, Jérome A1 - Jamora, Colin A1 - Chouaib, Salem AB -

Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.

VL - 13 IS - 3 ER - TY - JOUR T1 - Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library. JF - Cell Chem Biol Y1 - 2021 A1 - Emery, Amy A1 - Hardwick, Bryn S A1 - Crooks, Alex T A1 - Milech, Nadia A1 - Watt, Paul M A1 - Mithra, Chandan A1 - Kumar, Vikrant A1 - Giridharan, Saranya A1 - Sadasivam, Gayathri A1 - Mathivanan, Subashini A1 - Sudhakar, Sneha A1 - Bairy, Sneha A1 - Bharatham, Kavitha A1 - Hurakadli, Manjunath A A1 - Prasad, Thazhe K A1 - Kamariah, Neelagandan A1 - Muellner, Markus A1 - Coelho, Miguel A1 - Torrance, Christopher J A1 - McKenzie, Grahame J A1 - Venkitaraman, Ashok R AB -

Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3ε in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3ε, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.

ER - TY - JOUR T1 - Generation of a set of isogenic, gene-edited iPSC lines homozygous for all main APOE variants and an APOE knock-out line. JF - Stem Cell Res Y1 - 2019 A1 - Schmid, Benjamin A1 - Prehn, Kennie R A1 - Nimsanor, Natakarn A1 - Garcia, Blanca Irene Aldana A1 - Poulsen, Ulla A1 - Jørring, Ida A1 - Rasmussen, Mikkel A A1 - Clausen, Christian A1 - Mau-Holzmann, Ulrike A A1 - Ramakrishna, Sarayu A1 - Muddashetty, Ravi A1 - Steeg, Rachel A1 - Bruce, Kevin A1 - Mackintosh, Peter A1 - Ebneth, Andreas A1 - Holst, Bjørn A1 - Cabrera-Socorro, Alfredo AB -

Alzheimer's disease (AD) is the most frequent neurodegenerative disease amongst the elderly. The SNPs rs429358 and rs7412 in the APOE gene are the most common risk factor for sporadic AD, and there are three different alleles commonly referred to as APOE-ε2, APOE-ε3 and APOE-ε4. Induced pluripotent stem cells (iPSCs) hold great promise to model AD as such cells can be differentiated in vitro to the required cell type. Here we report the use of CRISPR/Cas9 technology employed on iPSCs from a healthy individual with an APOE-ε3/ε4 genotype to obtain isogenic APOE-ε2/ε2, APOE-ε3/ε3, APOE-ε4/ε4 lines as well as an APOE-knock-out line.

VL - 34 ER - TY - JOUR T1 - Towards an arthritis flare-responsive drug delivery system. JF - Nat Commun Y1 - 2018 A1 - Joshi, Nitin A1 - Yan, Jing A1 - Levy, Seth A1 - Bhagchandani, Sachin A1 - Slaughter, Kai V A1 - Sherman, Nicholas E A1 - Amirault, Julian A1 - Wang, Yufeng A1 - Riegel, Logan A1 - He, Xueyin A1 - Rui, Tan Shi A1 - Valic, Michael A1 - Vemula, Praveen K A1 - Miranda, Oscar R A1 - Levy, Oren A1 - Gravallese, Ellen M A1 - Aliprantis, Antonios O A1 - Ermann, Joerg A1 - Karp, Jeffrey M AB -

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.

VL - 9 IS - 1 ER - TY - JOUR T1 - The miR-124 family of microRNAs is crucial for regeneration of the brain and visual system in the planarian Schmidtea mediterranea JF - Development Y1 - 2017 A1 - Sasidharan, Vidyanand A1 - Marepally, Srujan A1 - Elliott, Sarah A. A1 - Baid, Srishti A1 - Lakshmanan, Vairavan A1 - Nayyar, Nishtha A1 - Bansal, Dhiru A1 - Sánchez Alvarado, Alejandro A1 - Vemula, Praveen Kumar A1 - Palakodeti, Dasaradhi AB -

Brain regeneration in planarians is mediated by precise spatiotemporal control of gene expression and is crucial for multiple aspects of neurogenesis. However, the mechanisms underpinning the gene regulation essential for brain regeneration are largely unknown. Here, we investigated the role of the miR-124 family of microRNAs in planarian brain regeneration. The miR-124 family (miR-124) is highly conserved in animals and regulates neurogenesis by facilitating neural differentiation, yet its role in neural wiring and brain organization is not known. We developed a novel method for delivering anti-miRs using liposomes for the functional knockdown of microRNAs. Smed-miR-124 knockdown revealed a key role for these microRNAs in neuronal organization during planarian brain regeneration. Our results also demonstrated an essential role for miR-124 in the generation of eye progenitors. Additionally, miR-124 regulates Smed-slit-1, which encodes an axon guidance protein, either by targeting slit-1 mRNA or, potentially, by modulating the canonical Notch pathway. Together, our results reveal a role for miR-124 in regulating the regeneration of a functional brain and visual system.

VL - 144 UR - http://dev.biologists.org/content/144/18/3211 ER -