Статті в журналах: "Manipulation (Therapeutics)"

1

Hao, Mengling, Jiabao Tang, Shengxiang Ge, Tingdong Li, and Ningshao Xia. "Bacterial-Artificial-Chromosome-Based Genome Editing Methods and the Applications in Herpesvirus Research." Microorganisms 11, no. 3 (February 26, 2023): 589. http://dx.doi.org/10.3390/microorganisms11030589.

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Herpesviruses are major pathogens that infect humans and animals. Manipulating the large genome is critical for exploring the function of specific genes and studying the pathogenesis of herpesviruses and developing novel anti-viral vaccines and therapeutics. Bacterial artificial chromosome (BAC) technology significantly advanced the capacity of herpesviruses researchers to manipulate the virus genomes. In the past years, advancements in BAC-based genome manipulating and screening strategies of recombinant BACs have been achieved, which has promoted the study of the herpes virus. This review summarizes the advances in BAC-based gene editing technology and selection strategies. The merits and drawbacks of BAC-based herpesvirus genome editing methods and the application of BAC-based genome manipulation in viral research are also discussed. This review provides references relevant for researchers in selecting gene editing methods in herpes virus research. Despite the achievements in the genome manipulation of the herpes viruses, the efficiency of BAC-based genome manipulation is still not satisfactory. This review also highlights the need for developing more efficient genome-manipulating methods for herpes viruses.

2

Almeida-Porada, Graça D. "Stem cell gene manipulation and delivery as systemic therapeutics." Advanced Drug Delivery Reviews 62, no. 12 (September 2010): 1139–40. http://dx.doi.org/10.1016/j.addr.2010.10.005.

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3

Juliano, Rudolph L. "Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery." Biomedicines 9, no. 5 (May 5, 2021): 512. http://dx.doi.org/10.3390/biomedicines9050512.

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Antisense oligonucleotides (ASOs), siRNA and splice switching oligonucleotides (SSOs) all have immense potential as therapeutic agents, potential that is now being validated as oligonucleotides enter the clinic. However, progress in oligonucleotide-based therapeutics has been limited by the difficulty in delivering these complex molecules to their sites of action in the cytosol or nucleus of cells within specific tissues. There are two aspects to the delivery problem. The first is that most types of oligonucleotides have poor uptake into non-hepatic tissues. The second is that much of the oligonucleotide that is taken up by cells is entrapped in endosomes where it is pharmacologically inert. It has become increasingly recognized that endosomal trapping is a key constraint on oligonucleotide therapeutics. Thus, many approaches have been devised to address this problem, primarily ones based on various nanoparticle technologies. However, recently an alternative approach has emerged that employs small molecules to manipulate intracellular trafficking processes so as to enhance oligonucleotide actions. This review presents the current status of this chemical biology approach to oligonucleotide delivery and seeks to point out possible paths for future development.

4

Wang, Ziyi, Pengchao Sun, Jingjing Su, Nan Zhang, Hongzhou Gu, and Yongxing Zhao. "DNA nanotechnology-facilitated ligand manipulation for targeted therapeutics and diagnostics." Journal of Controlled Release 340 (December 2021): 292–307. http://dx.doi.org/10.1016/j.jconrel.2021.11.004.

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5

Shanahan, Fergus. "Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Pathophysiological basis and prospects for probiotic therapy in inflammatory bowel disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 3 (March 2005): G417—G421. http://dx.doi.org/10.1152/ajpgi.00421.2004.

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Mechanisms underlying the conditioning influence of the intestinal flora on mucosal homeostasis, including development and function of immune responses, are attracting increasing scientific scrutiny. The intestinal flora is a positive asset to host defense, but some of its components may, in genetically susceptible hosts, become a risk factor for development of inflammatory bowel disease (IBD). It follows that strategies to enhance assets or offset microbial liabilities represent a therapeutic option; therein lies the rationale for manipulation of the flora in IBD. In addition, the diversity of regulatory signalling among the flora and host epithelum, lymphoid tissue, and neuromuscular apparatus is an untapped reservoir from which novel therapeutics may be mined. Moreover, the capacity to engineer food-grade or commensal bacteria to deliver therapeutic molecules to the intestinal mucosa promises to extend the scope of microbial manipulation for the benefit of mankind.

6

Papageorgiou, Maria, and Emmanuel Biver. "Interactions of the microbiome with pharmacological and non-pharmacological approaches for the management of ageing-related musculoskeletal diseases." Therapeutic Advances in Musculoskeletal Disease 13 (January 2021): 1759720X2110090. http://dx.doi.org/10.1177/1759720x211009018.

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Despite major progress in the understanding of the pathophysiology and therapeutic options for common ageing-related musculoskeletal conditions (i.e. osteoporosis and associated fractures, sarcopenia and osteoarthritis), there is still a considerable proportion of patients who respond sub optimally to available treatments or experience adverse effects. Emerging microbiome research suggests that perturbations in microbial composition, functional and metabolic capacity (i.e. dysbiosis) are associated with intestinal and extra-intestinal disorders including musculoskeletal diseases. Besides its contributions to disease pathogenesis, the role of the microbiome is further extended to shaping individuals’ responses to disease therapeutics (i.e. pharmacomicrobiomics). In this review, we focus on the reciprocal interactions between the microbiome and therapeutics for osteoporosis, sarcopenia and osteoarthritis. Specifically, we identify the effects of therapeutics on microbiome’s configurations, functions and metabolic output, intestinal integrity and immune function, but also the effects of the microbiome on the metabolism of these therapeutics, which in turn, may influence their bioavailability, efficacy and side-effect profile contributing to variable treatment responses in clinical practice. We further discuss emerging strategies for microbiota manipulation as preventive or therapeutic (alone or complementary to available treatments) approaches for improving outcomes of musculoskeletal health and disease.

7

Brown, Thomas J., and Victoria James. "The Role of Extracellular Vesicles in the Development of a Cancer Stem Cell Microenvironment Niche and Potential Therapeutic Targets: A Systematic Review." Cancers 13, no. 10 (May 18, 2021): 2435. http://dx.doi.org/10.3390/cancers13102435.

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Cancer stem cells (CSCs) have increasingly been shown to be a crucial element of heterogenous tumors. Although a relatively small component of the population, they increase the resistance to treatment and the likelihood of recurrence. In recent years, it has been shown, across multiple cancer types (e.g., colorectal, breast and prostate), that reciprocal communication between cancer and the microenvironment exists, which is, in part, facilitated by extracellular vesicles (EVs). However, the mechanisms of this method of communication and its influence on CSC populations is less well-understood. Therefore, the aim of this systematic review is to determine the evidence that supports the role of EVs in the manipulation of the tumor microenvironment to promote the survival of CSCs. Embase and PubMed were used to identify all studies on the topic, which were screened using PRISMA guidelines, resulting in the inclusion of 16 studies. These 16 studies reported on the EV content, pathways altered by EVs and therapeutic targeting of CSC through EV-mediated changes to the microenvironment. In conclusion, these studies demonstrated the role of EV-facilitated communication in maintaining CSCs via manipulation of the tumor microenvironment, demonstrating the potential of creating therapeutics to target CSCs. However, further works are needed to fully understand the targetable mechanisms upon which future therapeutics can be based.

8

Bondhopadhyay, Banashree, Sandeep Sisodiya, Faisal Abdulrahman Alzahrani, Muhammed A. Bakhrebah, Atul Chikara, Vishakha Kasherwal, Asiya Khan, et al. "Exosomes: A Forthcoming Era of Breast Cancer Therapeutics." Cancers 13, no. 18 (September 17, 2021): 4672. http://dx.doi.org/10.3390/cancers13184672.

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Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.

9

Mahajan, Kalpesh D., Gang Ruan, Greg Vieira, Thomas Porter, Jeffrey J. Chalmers, R. Sooryakumar, and Jessica O. Winter. "Biomolecular detection, tracking, and manipulation using a magnetic nanoparticle-quantum dot platform." Journal of Materials Chemistry B 8, no. 16 (2020): 3534–41. http://dx.doi.org/10.1039/c9tb02481f.

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Fluorescent and magnetic materials play a significant role in biosensor technology, enabling sensitive quantification and separations with applications in diagnostics, purification, quality control, and therapeutics.

10

Yang, Cai, Haitao Zhao, Yang Sun, Cheng Wang, Xinyao Geng, Ruowen Wang, Lumin Tang, Da Han, Jianjun Liu, and Weihong Tan. "Programmable manipulation of oligonucleotide–albumin interaction for elongated circulation time." Nucleic Acids Research 50, no. 6 (March 16, 2022): 3083–95. http://dx.doi.org/10.1093/nar/gkac156.

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Abstract Oligonucleotide (ON) therapeutics are emerging as a new generation of medicine with tremendous potential, but their clinical translation is hampered by inferior stability and short circulation time in the human body. Here, we report a general approach to manipulating the interaction between ONs and albumin by modulating hydrophobicity. A series of DNA aptamer derivatives were designed and prepared by programmable synthesis as an ON library with a gradient of hydrophobic base ‘F’. In vitro experiments revealed that the introduction of two F bases at both ends of ONs enhanced the biostability without sacrificing biological activities, while the binding affinity toward albumin was dramatically increased with Kd in the range of 100 nM to 1 μM. In vivo imaging confirmed the immediate formation of the aptamer–albumin complex after the injection, and the circulation time of the aptamer was dramatically elongated owing to the enhanced biostability and retarded renal excretion. The programmable incorporation of the F base provides a general approach to regulating albumin-binding affinity and enhancing the stability of aptamers in vivo, conferring aptamer therapeutics prolonged circulation time to meet clinical requirements.

11

Sweeney, Patrick, Michelle N. Bedenbaugh, Jose Maldonado, Pauline Pan, Katelyn Fowler, Savannah Y. Williams, Luis E. Gimenez, et al. "The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia." Science Translational Medicine 13, no. 590 (April 21, 2021): eabd6434. http://dx.doi.org/10.1126/scitranslmed.abd6434.

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Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

12

Schmidt, Paul J., Iva Toudjarska, Anoop K. Sendamarai, Tim Racie, Stuart Milstein, Brian R. Bettencourt, Julia Hettinger, David Bumcrot та Mark D. Fleming. "An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia". Blood 121, № 7 (14 лютого 2013): 1200–1208. http://dx.doi.org/10.1182/blood-2012-09-453977.

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Key Points Tmprss6 siRNA induces hepcidin and diminishes iron in hemochromatosis or thalassemia mice, improving the anemia seen in the latter model. Manipulation of TMPRSS6 with RNAi therapeutics may be an approach to treating iron overload diseases associated with low hepcidin levels.

13

Gilligan, Katie E., and Róisín M. Dwyer. "Extracellular Vesicles for Cancer Therapy: Impact of Host Immune Response." Cells 9, no. 1 (January 16, 2020): 224. http://dx.doi.org/10.3390/cells9010224.

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In recent times, extracellular vesicles (EVs) have come under the spotlight as potential therapeutics for cancer, due to the relative ease of manipulation of contents and potential for tumor targeting. The use of EVs as delivery vehicles may bypass some of the negative effects associated with cell-based carriers, and there has been a major focus on defining EV subtypes, establishing transparent nomenclature, and isolation and characterization techniques. EVs are believed to be a fingerprint of the secreting cell and so researchers harness the positive aspects of a particular cell of origin, and can then further modify EV contents to improve therapeutic efficacy. In this review, we highlight studies employing EVs as cancer therapeutics that have reported on immune response. As we rapidly advance towards potential application in the clinical setting, the question of immune response to EV administration in the cancer setting has become critically important.

14

Ferreira, Catia S. M., and Sotiris Missailidis. "Aptamer-based therapeutics and their potential in radiopharmaceutical design." Brazilian Archives of Biology and Technology 50, spe (September 2007): 63–76. http://dx.doi.org/10.1590/s1516-89132007000600008.

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Aptamers, short, single stranded oligonucleotide entities, have been developed in the past 15 years against a plethora of targets and for a variety of applications. These range from inhibition of receptors and enzymes to the identification of small molecules in sensor applications, and from the development of targeted therapeutic to the design of novel diagnostic and imaging agents. Furthermore, aptamers have been designed for targets that cover a wide range of diseases, from HIV to tropical diseases, cancer and inflammation. Their easy development and flexibility of use and manipulation, offers further potential. In this paper we review their selection and consider some of the recent applications of aptamers in the design of radiopharmaceuticals for the targeted radiotherapy and medical imaging of disease.

15

Wisniewski, T., D. R. Brown, and E. M. Sigurdsson. "Therapeutics in Alzheimer's and Prion Diseases." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 574–78. http://dx.doi.org/10.1042/bst0300574.

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There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the β-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-β peptide (sAβ) to Aβ plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrPc, to the disease-associated form, PrPsc. This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed ‘β-sheet breakers’ that directly target the abnormal conformational change both for Aβ- and PrPsc-related deposits. In addition, immune system activation can serve as β-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders.

16

Slaby, Ondrej, Richard Laga, and Ondrej Sedlacek. "Therapeutic targeting of non-coding RNAs in cancer." Biochemical Journal 474, no. 24 (December 14, 2017): 4219–51. http://dx.doi.org/10.1042/bcj20170079.

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The majority of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) affect normal expression of the genes, including oncogenes and tumour suppressive genes, which make them a new class of targets for drug development in cancer. Although microRNAs (miRNAs) are the most studied regulatory ncRNAs to date, and miRNA-targeted therapeutics have already reached clinical development, including the mimics of the tumour suppressive miRNAs miR-34 and miR-16, which reached phase I clinical trials for the treatment of liver cancer and mesothelioma, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognised. Here, we describe obstacles and advances in the development of ncRNA therapeutics and provide the comprehensive overview of the ncRNA chemistry and delivery technologies. Furthermore, we summarise recent knowledge on the biological functions of miRNAs and their involvement in carcinogenesis, and discuss the strategies of their therapeutic manipulation in cancer. We review also the emerging insights into the role of lncRNAs and their potential as targets for novel treatment paradigms. Finally, we provide the up-to-date summary of clinical trials involving miRNAs and future directions in the development of ncRNA therapeutics.

17

Dasgupta, Ishani, and Anushila Chatterjee. "Recent Advances in miRNA Delivery Systems." Methods and Protocols 4, no. 1 (January 20, 2021): 10. http://dx.doi.org/10.3390/mps4010010.

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MicroRNAs (miRNAs) represent a family of short non-coding regulatory RNA molecules that are produced in a tissue and time-specific manner to orchestrate gene expression post-transcription. MiRNAs hybridize to target mRNA(s) to induce translation repression or mRNA degradation. Functional studies have demonstrated that miRNAs are engaged in virtually every physiological process and, consequently, miRNA dysregulations have been linked to multiple human pathologies. Thus, miRNA mimics and anti-miRNAs that restore miRNA expression or downregulate aberrantly expressed miRNAs, respectively, are highly sought-after therapeutic strategies for effective manipulation of miRNA levels. In this regard, carrier vehicles that facilitate proficient and safe delivery of miRNA-based therapeutics are fundamental to the clinical success of these pharmaceuticals. Here, we highlight the strengths and weaknesses of current state-of-the-art viral and non-viral miRNA delivery systems and provide perspective on how these tools can be exploited to improve the outcomes of miRNA-based therapeutics.

18

Zha, Jun, Jinjing Li, Shihui Fan, Zengping Duan, Yibing Zhao, and Chuanliu Wu. "An evolution-inspired strategy to design disulfide-rich peptides tolerant to extensive sequence manipulation." Chemical Science 12, no. 34 (2021): 11464–72. http://dx.doi.org/10.1039/d1sc02952e.

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A general method was developed to design multicyclic peptides with diverse disulfide frameworks amenable to random peptide library design, enabling the development of new disulfide-rich peptide ligands and therapeutics with structures not derived from natural peptides.

19

Yamamoto, Tsuyoshi, and Asako Yamayoshi. "Physicochemical Manipulation for Effective Nucleic Acid Therapeutics -Toward Material Symbiosis with Nucleic Acid Drugs-." Drug Delivery System 37, no. 2 (March 25, 2022): 131–41. http://dx.doi.org/10.2745/dds.37.131.

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20

Rani, Vibha, Shivani Singhal, Kumkum Sharma, Rohan Vaid, Kanishka Aggarwal, Renu Bhadana, Radhika Agarwal, and Neha Atale. "Human Gut Microbiome: A New Frontier in Cancer Diagnostics & Therapeutics." Current Pharmaceutical Design 27, no. 45 (November 19, 2021): 4578–92. http://dx.doi.org/10.2174/1381612827666211006152112.

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The field of oncology is vast and ever-growing. The present cancer therapeutics is continually exhibiting various drawbacks, which opens the door for exploring better novel therapeutic techniques. One such emerging technique is the manipulation of gut microbiota to induce a positive curative effect in the body. The dynamic gut microbiota of our body houses an astonishing number of microorganisms, mainly bacteria. The balance of the gut microbiota is essential for good health as imbalances may result in dysbiosis leading to various diseases such as cancer. The gut microbiota can be manipulated by using prebiotics, probiotics, synbiotics, postbiotics, and antibiotics for better therapeutic outcomes, as well as to improve the quality of life of patients undergoing conventional cancer treatment. Administration of bacteria as a probiotic agent accompanied with prebiotics obtained from a wide variety of herbs has been used effectively to enhance the treatment of various cancers. Although the theoretical basis of Gut therapy can be ascertained, further clinical trials will be essential to determine the scope and limitations fully. The present review provides a glimpse of conventional and novel cancer therapeutics and their drawbacks, along with the role of the gut microbiome and its modulation to design new pharmaceutics against cancer.

21

Shinde, Pallavi, Loganathan Mohan, Amogh Kumar, Koyel Dey, Anjali Maddi, Alexander Patananan, Fan-Gang Tseng, Hwan-You Chang, Moeto Nagai, and Tuhin Santra. "Current Trends of Microfluidic Single-Cell Technologies." International Journal of Molecular Sciences 19, no. 10 (October 12, 2018): 3143. http://dx.doi.org/10.3390/ijms19103143.

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The investigation of human disease mechanisms is difficult due to the heterogeneity in gene expression and the physiological state of cells in a given population. In comparison to bulk cell measurements, single-cell measurement technologies can provide a better understanding of the interactions among molecules, organelles, cells, and the microenvironment, which can aid in the development of therapeutics and diagnostic tools. In recent years, single-cell technologies have become increasingly robust and accessible, although limitations exist. In this review, we describe the recent advances in single-cell technologies and their applications in single-cell manipulation, diagnosis, and therapeutics development.

22

Duong, Mai Thi-Quynh, Yeshan Qin, Sung-Hwan You, and Jung-Joon Min. "Bacteria-cancer interactions: bacteria-based cancer therapy." Experimental & Molecular Medicine 51, no. 12 (December 2019): 1–15. http://dx.doi.org/10.1038/s12276-019-0297-0.

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AbstractRecent advances in cancer therapeutics, such as targeted therapy and immunotherapy, have raised the hope for cures for many cancer types. However, there are still ongoing challenges to the pursuit of novel therapeutic approaches, including high toxicity to normal tissue and cells, difficulties in treating deep tumor tissue, and the possibility of drug resistance in tumor cells. The use of live tumor-targeting bacteria provides a unique therapeutic option that meets these challenges. Compared with most other therapeutics, tumor-targeting bacteria have versatile capabilities for suppressing cancer. Bacteria preferentially accumulate and proliferate within tumors, where they can initiate antitumor immune responses. Bacteria can be further programmed via simple genetic manipulation or sophisticated synthetic bioengineering to produce and deliver anticancer agents based on clinical needs. Therapeutic approaches using live tumor-targeting bacteria can be applied either as a monotherapy or in combination with other anticancer therapies to achieve better clinical outcomes. In this review, we introduce and summarize the potential benefits and challenges of this anticancer approach. We further discuss how live bacteria interact with tumor microenvironments to induce tumor regression. We also provide examples of different methods for engineering bacteria to improve efficacy and safety. Finally, we introduce past and ongoing clinical trials involving tumor-targeting bacteria.

23

Zheng, Mingjie, Joan Jacob, Shao-Hsi Hung, and Jun Wang. "The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart." Biomolecules 10, no. 7 (July 10, 2020): 1024. http://dx.doi.org/10.3390/biom10071024.

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Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new feasible therapeutic avenues for cardiac repair. The Hippo pathway, a fundamental pathway with pivotal roles in cell proliferation, survival and differentiation, has tremendous potential for therapeutic manipulation in cardiac regeneration. In this review, we summarize the most recent studies that have revealed the function of the Hippo pathway in heart regeneration and homeostasis. In particular, we discuss the molecular mechanisms of how the Hippo pathway maintains cardiac homeostasis by directing cardiomyocyte chromatin remodeling and regulating the cell-cell communication between cardiomyocytes and non-cardiomyocytes in the heart.

24

Teo, Min Yuen, Dana E. Rathkopf, and Philip Kantoff. "Treatment of Advanced Prostate Cancer." Annual Review of Medicine 70, no. 1 (January 27, 2019): 479–99. http://dx.doi.org/10.1146/annurev-med-051517-011947.

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The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.

25

Poirot, Laurent, Cécile Schiffer-Mannioui, Brian Philip, Sophie Derniame, Agnes Gouble, Isabelle Chion-Sotinel, Diane Le Clerre, et al. "T-Cell Engineering For “off-The-shelf” Adoptive Immunotherapy." Blood 122, no. 21 (November 15, 2013): 1661. http://dx.doi.org/10.1182/blood.v122.21.1661.1661.

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Abstract Adoptive T-cell therapies, where exogenous expression of a chimeric antigen receptor (CAR) confers cancer recognition, have shown significant promise in initial clinical trials. However, present adoptive immunotherapy Methods are limited by the need for manipulation of autologous patient T-cells. To permit such an approach in an allogeneic context, Transcription Activator-Like Effector Nucleases (TALENTM) have been used to simultaneously inactivate the endogenous T cell receptor and CD52, a cellular target for a lymphodepleting treatment. This approach reduces the risk of GVHD while permitting proliferation and activity of the introduced T lymphocytes in the presence of the immunosuppressive drug alemtuzumab. Electroporation of primary T cells with mRNA coding for the appropriate TALENTM result in double knock-out (dKO) frequencies of up to 70%. Furthermore, functional characterization demonstrates that the dKO cells are resistant to complement dependent lysis or in vivo depletion by alemtuzumab, and show no apparent potential for TCR-mediated activation. Finally, endowing the dKO cells with a CD19 CAR supports their capacity to kill CD19+ tumor targets as efficiently as unedited T-cells both in vitro and in vivo. Disclosures: Poirot: CELLECTIS THERAPEUTICS: Employment. Schiffer-Mannioui:CELLECTIS THERAPEUTICS: Employment. Philip:UCL Cancer Institute, London, United Kingdom: Employment. Derniame:CELLECTIS THERAPEUTICS: Employment. Gouble:CELLECTIS THERAPEUTICS: Employment. Chion-Sotinel:CELLECTIS THERAPEUTICS: Employment. Le Clerre:CELLECTIS THERAPEUTICS: Employment. Lemaire:CELLECTIS THERAPEUTICS: Employment. Grosse:CELLECTIS THERAPEUTICS: Employment. Cheung:UCL Cancer Institute, London, United Kingdom: Employment. Arnould:CELLECTIS THERAPEUTICS: Employment. Smith:CELLECTIS THERAPEUTICS: Employment. Pule:UCL Cancer Institute, London, United Kingdom: Employment. Scharenberg:CELLECTIS THERAPEUTICS: Employment.

26

Nguyen, Thuy, Brian F. Thomas, and Yanan Zhang. "Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development." Current Topics in Medicinal Chemistry 19, no. 16 (September 16, 2019): 1418–35. http://dx.doi.org/10.2174/1568026619666190708164841.

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The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the CB1R in the last two decades.

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Yagi, Yusuke, Takamasa Teramoto, Shuji Kaieda, Takayoshi Imai, Tadamasa Sasaki, Maiko Yagi, Nana Maekawa, and Takahiro Nakamura. "Construction of A Versatile, Programmable RNA-binding Protein using Designer PPR Proteins and Its Application for Splicing Control in Mammalian Cells." Cells 11, no. 22 (November 8, 2022): 3529. http://dx.doi.org/10.3390/cells11223529.

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RNAs play many essential roles in gene expression and are involved in various human diseases. Although genome editing technologies have been established, the engineering of sequence-specific RNA-binding proteins that manipulate particular cellular RNA molecules is immature, in contrast to nucleotide-based RNA manipulation technology, such as siRNA- and RNA-targeting CRISPR/Cas. Here, we demonstrate a versatile RNA manipulation technology using pentatricopeptide-repeat (PPR)-motif-containing proteins. First, we developed a rapid construction and evaluation method for PPR-based designer sequence-specific RNA-binding proteins. This system has enabled the steady construction of dozens of functional designer PPR proteins targeting long 18 nt RNA, which targets a single specific RNA in the mammalian transcriptome. Furthermore, the cellular functionality of the designer PPR proteins was first demonstrated by the control of alternative splicing of either a reporter gene or an endogenous CHK1 mRNA. Our results present a versatile protein-based RNA manipulation technology using PPR proteins that facilitates the understanding of unknown RNA functions and the creation of gene circuits and has potential for use in future therapeutics.

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Kao, Ting-Wei, and Chin-Chou Huang. "Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases." International Journal of Molecular Sciences 23, no. 2 (January 12, 2022): 804. http://dx.doi.org/10.3390/ijms23020804.

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Phenotyping cardiovascular illness and recognising heterogeneities within are pivotal in the contemporary era. Besides traditional risk factors, accumulated evidence suggested that a high inflammatory burden has emerged as a key characteristic modulating both the pathogenesis and progression of cardiovascular diseases, inclusive of atherosclerosis and myocardial infarction. To mechanistically elucidate the correlation, signalling pathways downstream to Toll-like receptors, nucleotide oligomerisation domain-like receptors, interleukins, tumour necrosis factor, and corresponding cytokines were raised as central mechanisms exerting the effect of inflammation. Other remarkable adjuvant factors include oxidative stress and secondary ferroptosis. These molecular discoveries have propelled pharmaceutical advancements. Statin was suggested to confer cardiovascular benefits not only by lowering cholesterol levels but also by attenuating inflammation. Colchicine was repurposed as an immunomodulator co-administered with coronary intervention. Novel interleukin-1β and −6 antagonists exhibited promising cardiac benefits in the recent trials as well. Moreover, manipulation of gut microbiota and associated metabolites was addressed to antagonise inflammation-related cardiovascular pathophysiology. The gut-cardio-renal axis was therein established to explain the mutual interrelationship. As for future perspectives, artificial intelligence in conjunction with machine learning could better elucidate the sequencing of the microbiome and data mining. Comprehensively understanding the interplay between the gut microbiome and its cardiovascular impact will help identify future therapeutic targets, affording holistic care for patients with cardiovascular diseases.

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Fujiwara, Yusuke, Yuki Yamanashi, Akiko Fujimura, Yuko Sato, Tomoya Kujirai, Hitoshi Kurumizaka, Hiroshi Kimura, Kenzo Yamatsugu, Shigehiro A. Kawashima, and Motomu Kanai. "Live-cell epigenome manipulation by synthetic histone acetylation catalyst system." Proceedings of the National Academy of Sciences 118, no. 4 (January 19, 2021): e2019554118. http://dx.doi.org/10.1073/pnas.2019554118.

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Chemical modifications of histones, such as lysine acetylation and ubiquitination, play pivotal roles in epigenetic regulation of gene expression. Methods to alter the epigenome thus hold promise as tools for elucidating epigenetic mechanisms and as therapeutics. However, an entirely chemical method to introduce histone modifications in living cells without genetic manipulation is unprecedented. Here, we developed a chemical catalyst, PEG-LANA-DSSMe 11, that binds with nucleosome’s acidic patch and promotes regioselective, synthetic histone acetylation at H2BK120 in living cells. The size of polyethylene glycol in the catalyst was a critical determinant for its in-cell metabolic stability, binding affinity to histones, and high activity. The synthetic acetylation promoted by 11 without genetic manipulation competed with and suppressed physiological H2B ubiquitination, a mark regulating chromatin functions, such as transcription and DNA damage response. Thus, the chemical catalyst will be a useful tool to manipulate epigenome for unraveling epigenetic mechanisms in living cells.

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Dodson, Matthew, Montserrat Rojo de la Vega, Aram B. Cholanians, Cody J. Schmidlin, Eli Chapman, and Donna D. Zhang. "Modulating NRF2 in Disease: Timing Is Everything." Annual Review of Pharmacology and Toxicology 59, no. 1 (January 6, 2019): 555–75. http://dx.doi.org/10.1146/annurev-pharmtox-010818-021856.

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The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials.

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Winter, Ann, Lois A. Salamonsen, and Jemma Evans. "Modelling fibroid pathology: development and manipulation of a myometrial smooth muscle cell macromolecular crowding model to alter extracellular matrix deposition." Molecular Human Reproduction 26, no. 7 (May 25, 2020): 498–509. http://dx.doi.org/10.1093/molehr/gaaa036.

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ABSTRACT Current treatment options for uterine fibroids are limited to hormonal manipulation or surgical intervention. We aimed to develop an in vitro model to mirror collagen deposition and extracellular matrix (ECM) formation, the principal features of uterine fibroids, to enable testing of novel therapeutics. Macromolecular crowding with Ficoll 400 and Ficoll 70 in cultures of human uterine myometrial smooth muscle cells containing ascorbic acid, provided the basis for this model. These culture conditions mimic the ‘crowded’ nature of the in vivo extracellular environment by incorporating neutral, space-filling macromolecules into conventional cell cultures. This method of culture facilitates appropriate ECM deposition, thus closely representing the in vivo fibrotic phenotype of uterine fibroids. Macromolecular crowding in Ficoll cultures containing ascorbic acid reduced myometrial smooth muscle cell proliferation and promoted collagen production. Under these conditions, collagen was processed for extracellular deposition as demonstrated by C-propeptide cleavage from secreted procollagen. The fibrosis marker activin was increased relative to its natural inhibitor, follistatin, in crowded culture conditions while addition of exogenous follistatin reduced collagen (Col1A1) gene expression. This in vitro model represents a promising development for the testing of therapeutic interventions for uterine fibroids. However, it does not recapitulate the full in vivo pathology which can include specific genetic and epigenetic alterations that have not been identified in the myometrial smooth muscle (hTERT-HM) cell line. Following screening of potential therapeutics using the model, the most promising compounds will require further assessment in the context of individual subjects including those with genetic changes implicated in fibroid pathogenesis.

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Mathew, Robins, Robert McGee, Kevin Roche, Shada Warreth, and Nikolaos Papakostas. "Introducing Mobile Collaborative Robots into Bioprocessing Environments: Personalised Drug Manufacturing and Environmental Monitoring." Applied Sciences 12, no. 21 (October 27, 2022): 10895. http://dx.doi.org/10.3390/app122110895.

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Personalised therapeutic drugs are the future of the medical drug sector. For manufacturers, this will require the flexibility to produce many different unique batches within a given facility. This research paper aims to demonstrate the potential of mobile collaborative robots for improving current manufacturing practices in personalised therapeutics. The benefits and challenges of introducing robots in biologics are explored, including current practices, limitations, likely future practices, and the market outlook. Experiments demonstrating the application of a mobile collaborative robot to perform three different routine tasks is presented. These experiments include the transport of centrifugal tubes, manipulation of infusion bags, and scanning of Petri dishes for environmental monitoring. The investigations highlight the potential of collaborative mobile robotic platforms for automating the routine tasks carried out within the biomanufacturing sector.

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Allen, Ashley B., Josh A. Zimmermann, Olivia A. Burnsed, Doron Cohn Yakubovich, Hazel Y. Stevens, Zulma Gazit, Todd C. McDevitt, and Robert E. Guldberg. "Environmental manipulation to promote stem cell survival in vivo: use of aggregation, oxygen carrier, and BMP-2 co-delivery strategies." Journal of Materials Chemistry B 4, no. 20 (2016): 3594–607. http://dx.doi.org/10.1039/c5tb02471d.

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While mesenchymal stem cell (MSC)-based strategies for critically-sized bone defect repair hold promise, poor cell survival in vivo remains a significant barrier to the translation of these therapeutics.

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Gilham, Dean, Audrey L. Smith, Li Fu, Dalia Y. Moore, Abenaya Muralidharan, St Patrick M. Reid, Stephanie C. Stotz, et al. "Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro." Biomedicines 9, no. 4 (April 18, 2021): 437. http://dx.doi.org/10.3390/biomedicines9040437.

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Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

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Hashizume, Atsushi, Kenneth H. Fischbeck, Maria Pennuto, Pietro Fratta, and Masahisa Katsuno. "Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 10 (September 15, 2020): 1085–91. http://dx.doi.org/10.1136/jnnp-2020-322949.

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Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

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Wang, Julie, Junlong Dang, and Song Guo Zheng. "Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39-CD73 signaling pathway." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 236.13. http://dx.doi.org/10.4049/jimmunol.204.supp.236.13.

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Abstract Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptively transferred GMSC home to and maintain in the kidney and have a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogated the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

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Campbell, Jarryd M., Katherine A. Hartjes, Timothy J. Nelson, Xiaolei Xu, and Stephen C. Ekker. "New and TALENted Genome Engineering Toolbox." Circulation Research 113, no. 5 (August 16, 2013): 571–87. http://dx.doi.org/10.1161/circresaha.113.301765.

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Recent advances in the burgeoning field of genome engineering are accelerating the realization of personalized therapeutics for cardiovascular disease. In the postgenomic era, sequence-specific gene-editing tools enable the functional analysis of genetic alterations implicated in disease. In partnership with high-throughput model systems, efficient gene manipulation provides an increasingly powerful toolkit to study phenotypes associated with patient-specific genetic defects. Herein, this review emphasizes the latest developments in genome engineering and how applications within the field are transforming our understanding of personalized medicine with an emphasis on cardiovascular diseases.

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Pacheco, David Rincon Fernandez, Hannah Park, Katie Grausam, and Joshua Breunig. "NGMA-4. Creation of a MADR brain tumor single-cell atlas for examination of inter-/intratumor heterogeneity and the results of genetic perturbations in a diverse array of brain tumor subtypes." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii5. http://dx.doi.org/10.1093/noajnl/vdab070.019.

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Abstract We have recently established mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. MADR provides a toolkit of elements for combinatorial labeling, inducible/reversible transgene manipulation, VCre recombinase expression, and genetic manipulation of human cells. Further, we have demonstrated the versatility of MADR by creating glioma models with mixed, reporter-identified zygosity or with “personalized” driver mutations from pediatric glioma. For example, introducing H3f3a (aka H3.3) mutation variants with MADR regulates the spatiotemporal profile of glioma, and single-cell RNA and ATAC sequencing analysis demonstrates a recapitulation of developmental hierarchy seen in K27M mutant human glioma. Moreover, we have generated novel models of H3.3 WT glioma, H3.3 G34R glioma, and supratentorial ependymoma using patient-derived oncofusion transgenes. These models display a high degree of phenotypic fidelity and we now compare these models on a single-cell level with our previous models, mouse single-cell RNA glioma datasets from other studies, and human tumor cell transcriptomes. Our multi-omics approach includes integration of ChIP-seq/Cut&Tag datasets, single-cell ATAC, and single-cell Cut&Tag datasets. Moreover, we have engineered a novel methodology for inducible gain- and loss-of function perturbation studies in vivo. Using ETS transcription factors as a proof-of-principle, we overlay these genetic perturbations on the glioma atlas to examine the gene networks altered by precise molecular manipulations. We hope that these combined approaches will enable researchers to discover disease mechanisms with increased resolution and test therapeutics in credentialed pre-clinical disease models.

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Guru Murthy, Guru Subramanian, Brent R. Logan, Stephanie Bo-Subait, Amer Beitingjaneh, Steven Devine, Nosha Farhadfar, Lohith Gowda, et al. "Major ABO Incompatibility Significantly Influences the Survival and Outcomes after Allogeneic Hematopoietic Cell Transplantation in Leukemia - CIBMTR Analysis." Blood 138, Supplement 1 (November 5, 2021): 907. http://dx.doi.org/10.1182/blood-2021-150635.

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Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT in these leukemias, the independent impact of ABO mismatching between the patient and donor remains unclear. Methods: Using the CIBMTR database, we identified adults aged ≥18 years with AML or ALL who underwent allo-HCT from HLA-matched sibling donor (MSD) or 8/8 matched unrelated donor (MUD) between 2008-2018. We excluded patients who underwent transplant from a mismatched donor source or who received an ex-vivo T-cell depleted graft. Patients were stratified into cohorts based on ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Outcomes such as overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, incidence of acute graft versus host disease (GVHD), chronic GVHD, neutrophil engraftment, platelet engraftment and graft failure were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariate regression model included main effect (ABO status) and covariates (patient age, gender match, disease type, disease status, HCT-CI, Karnofsky performance status, donor type, conditioning intensity/use of TBI, stem cell source, GVHD prophylaxis, ATG/alemtuzumab use, transplant year). Results: Of 4946 patients who met the study criteria, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had minor ABO mismatch, 899 patients (18.1%) had major ABO mismatch and 276 patients (5.6%) had bidirectional ABO mismatch. Graft manipulation for ABO incompatibility was performed in 900 patients (minor ABO mismatch=532; major ABO mismatch=226; bidirectional mismatch=142), however, the information on individual graft manipulation techniques was limited. In multivariable analysis (table 1), major ABO mismatch significantly affected the OS, platelet engraftment and primary graft failure. Compared to ABO matched allo-HCT, major ABO mismatched allo-HCT was associated with worse OS (major mismatch - HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p=<0.001), and higher risk of primary graft failure [4.5% (major mismatch) vs. 3.2% (ABO matched) - HR 1.60, 95% CI 1.12-2.30, p=0.01]. There was a significant interaction between the ABO status and graft type (peripheral blood vs. bone marrow) for the acute GVHD grades 2-4 model, and they are presented separately (table 1). Bidirectional ABO mismatch also significantly impacted the outcomes such as acute GVHD grades 2-4 (in bone marrow stem cell subgroup, HR 0.50, 95%CI 0.27-0.93, p=0.02) in addition to a trend towards inferior survival and NRM (p-value not significant). Other outcomes such as relapse (p=0.41), acute GVHD grades 3-4 (p=0.13), and chronic GVHD (p=0.30) were not significantly influenced by the ABO status. Conclusions: Our study demonstrates that pre-transplant ABO status is an independent predictor of survival and other post-transplant outcomes in a large cohort of patients with AML and ALL undergoing allo-HCT in the recent era. This demonstrates the importance of considering ABO status in the donor selection algorithms and potential strategies to mitigate its adverse impact. Due to the limited information available on graft manipulation strategies, the impact of graft manipulation techniques on the outcomes could not be evaluated and needs to be investigated in future studies. Figure 1 Figure 1. Disclosures Guru Murthy: Techspert: Consultancy; Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Qessential: Consultancy; TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Farhadfar: Incyte: Consultancy. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria. Stefanski: Novartis: Honoraria. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

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He, Buyuan, James T. Tran, and David Jesse Sanchez. "Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses." Journal of Immunology Research 2019 (April 4, 2019): 1–10. http://dx.doi.org/10.1155/2019/8685312.

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Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.

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Köhler, Cristiano A., André F. Carvalho, Gilberto S. Alves, Roger S. McIntyre, Thomas N. Hyphantis, and Martín Cammarota. "Autobiographical Memory Disturbances in Depression: A Novel Therapeutic Target?" Neural Plasticity 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/759139.

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Major depressive disorder (MDD) is characterized by a dysfunctional processing of autobiographical memories. We review the following core domains of deficit: systematic biases favoring materials of negative emotional valence; diminished access and response to positive memories; a recollection of overgeneral memories in detriment of specific autobiographical memories; and the role of ruminative processes and avoidance when dealing with autobiographical memories. Furthermore, we review evidence from functional neuroimaging studies of neural circuits activated by the recollection of autobiographical memories in both healthy and depressive individuals. Disruptions in autobiographical memories predispose and portend onset and maintenance of depression. Thus, we discuss emerging therapeutics that target memory difficulties in those with depression. We review strategies for this clinical domain, including memory specificity training, method-of-loci, memory rescripting, and real-time fMRI neurofeedback training of amygdala activity in depression. We propose that the manipulation of the reconsolidation of autobiographical memories in depression might represent a novel yet largely unexplored, domain-specific, therapeutic opportunity for depression treatment.

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Zhang, Peiran, Hunter Bachman, Adem Ozcelik, and Tony Jun Huang. "Acoustic Microfluidics." Annual Review of Analytical Chemistry 13, no. 1 (June 12, 2020): 17–43. http://dx.doi.org/10.1146/annurev-anchem-090919-102205.

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Acoustic microfluidic devices are powerful tools that use sound waves to manipulate micro- or nanoscale objects or fluids in analytical chemistry and biomedicine. Their simple device designs, biocompatible and contactless operation, and label-free nature are all characteristics that make acoustic microfluidic devices ideal platforms for fundamental research, diagnostics, and therapeutics. Herein, we summarize the physical principles underlying acoustic microfluidics and review their applications, with particular emphasis on the manipulation of macromolecules, cells, particles, model organisms, and fluidic flows. We also present future goals of this technology in analytical chemistry and biomedical research, as well as challenges and opportunities.

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Sorolla, Anabel, Edina Wang, Emily Golden, Ciara Duffy, Sónia T. Henriques, Andrew D. Redfern, and Pilar Blancafort. "Precision medicine by designer interference peptides: applications in oncology and molecular therapeutics." Oncogene 39, no. 6 (October 21, 2019): 1167–84. http://dx.doi.org/10.1038/s41388-019-1056-3.

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Abstract In molecular cancer therapeutics only 10% of known cancer gene products are targetable with current pharmacological agents. Major oncogenic drivers, such as MYC and KRAS proteins are frequently highly overexpressed or mutated in multiple human malignancies. However, despite their key role in oncogenesis, these proteins are hard to target with traditional small molecule drugs due to their large, featureless protein interfaces and lack of deep pockets. In addition, they are inaccessible to large biologicals, which are unable to cross cell membranes. Designer interference peptides (iPeps) represent emerging pharmacological agents created to block selective interactions between protein partners that are difficult to target with conventional small molecule chemicals or with large biologicals. iPeps have demonstrated successful inhibition of multiple oncogenic drivers with some now entering clinical settings. However, the clinical translation of iPeps has been hampered by certain intrinsic limitations including intracellular localization, targeting tissue specificity and pharmacological potency. Herein, we outline recent advances for the selective inhibition of major cancer oncoproteins via iPep approaches and discuss the development of multimodal peptides to overcome limitations of the first generations of iPeps. Since many protein–protein interfaces are cell-type specific, this approach opens the door to novel programmable, precision medicine tools in cancer research and treatment for selective manipulation and reprogramming of the cancer cell oncoproteome.

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Yang, Ji Won, Yoojin Seo, Tae-Hoon Shin, Ji-Su Ahn, Su-Jeong Oh, Ye Young Shin, Min-Jung Kang, et al. "Extracellular Vesicles from SOD3-Transduced Stem Cells Exhibit Improved Immunomodulatory Abilities in the Murine Dermatitis Model." Antioxidants 9, no. 11 (November 23, 2020): 1165. http://dx.doi.org/10.3390/antiox9111165.

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The immunoregulatory abilities of mesenchymal stem cells (MSCs) have been investigated in various autoimmune and allergic diseases. However, the therapeutic benefits observed in preclinical settings have not been reproducible in clinical trials. This discrepancy is due to insufficient efficacy of MSCs in harsh microenvironments, as well as batch-dependent variability in potency. Therefore, to achieve more beneficial and uniform outcomes, novel strategies are required to potentiate the therapeutic effect of MSCs. One of simple strategies to augment cellular function is genetic manipulation. Several studies showed that transduction of antioxidant enzyme into cells can increase anti-inflammatory effects. Therefore, we evaluated the immunoregulatory abilities of MSCs introduced with extracellular superoxide dismutase 3 (SOD3) in the present study. SOD3-overexpressed MSCs (SOD3-MSCs) reduced the symptoms of murine model of atopic dermatitis (AD)-like inflammation, as well as the differentiation and activation of various immune cells involved in AD progression. Interestingly, extracellular vesicles (EVs) isolated from SOD3-MSCs delivered SOD3 protein. EVs carrying SOD3 also exerted improved therapeutic efficacy, as observed in their parent cells. These results suggest that MSCs transduced with SOD3, an antioxidant enzyme, as well as EVs isolated from modified cells, might be developed as a promising cell-based therapeutics for inflammatory disorders.

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Alberti, Michael, Jessy Deshane, Larisa Pereboeva, Yuko Tsuruta, Ed Abraham, David Chaplin, Stanton Gerson, David Curiel, and Justin Roth. "A recombinant adenovirus for targeted gene therapy of pulmonary inflammation (155.23)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 155.23. http://dx.doi.org/10.4049/jimmunol.186.supp.155.23.

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Abstract Inflammation is a pathological component of many debilitating lung diseases. Thus, therapeutics that suppress the inflammatory response should also minimize inflammation-induced airway destruction. In this regard, Adenovirus type 5 (Ad5) vectors have a long history as therapeutic agents, due to their in vivo stability and amenability to genetic manipulation. Since circulating leukocytes infiltrate and mediate damage to the sites of pathology, we proposed to modulate Ad5 tropism to the dense leukocyte pool in the lung microvasculature for localized therapeutic intervention of inflammation. However, leukocytes do not express the coxsackie and adenovirus receptor (CAR) and are thus resistant to Ad5 infection. Therefore, we utilized phage display to identify a myeloid-binding peptide (MBP) and then genetically incorporated this sequence into an Ad5 fiber lacking the native CAR-binding domain (knob). Non-replicative Ad reporter vectors containing these MBP-fibers (Ad.MBP) maintained myeloid-binding specificity, and upon intravenous delivery the altered tropism enhanced lung gene transfer by five orders of magnitude over that obtained with unmodified Ad5. Disparity between cell types bound and those transduced suggest Ad.MBP is first sequestered by circulating leukocytes and subsequently “handed-off” to transduce pulmonary endothelium. These studies highlight the importance of pulmonary leukocytes as a target for therapeutic delivery in inflammatory lung disease.

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Guilherme, Malena dos Santos, Vu Thu Thuy Nguyen, Christoph Reinhardt, and Kristina Endres. "Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer’s Disease-Like Pathology." Microorganisms 9, no. 4 (April 13, 2021): 815. http://dx.doi.org/10.3390/microorganisms9040815.

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The gut brain axis seems to modulate various psychiatric and neurological disorders such as Alzheimer’s disease (AD). Growing evidence has led to the assumption that the gut microbiome might contribute to or even present the nucleus of origin for these diseases. In this regard, modifiers of the microbial composition might provide attractive new therapeutics. Aim of our study was to elucidate the effect of a rigorously changed gut microbiome on pathological hallmarks of AD. 5xFAD model mice were treated by antibiotics or probiotics (L. acidophilus and L. rhamnosus) for 14 weeks. Pathogenesis was measured by nest building capability and plaque deposition. The gut microbiome was affected as expected: antibiotics significantly reduced viable commensals, while probiotics transiently increased Lactobacillaceae. Nesting score, however, was only improved in antibiotics-treated mice. These animals additionally displayed reduced plaque load in the hippocampus. While various physiological parameters were not affected, blood sugar was reduced and serum glucagon level significantly elevated in the antibiotics-treated animals together with a reduction in the receptor for advanced glycation end products RAGE—the inward transporter of Aβ peptides of the brain. Assumedly, the beneficial effect of the antibiotics was based on their anti-diabetic potential.

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Shin, Yuseon, Patihul Husni, Kioh Kang, Dayoon Lee, Sehwa Lee, Eunseong Lee, Yuseok Youn, and Kyungtaek Oh. "Recent Advances in pH- or/and Photo-Responsive Nanovehicles." Pharmaceutics 13, no. 5 (May 14, 2021): 725. http://dx.doi.org/10.3390/pharmaceutics13050725.

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The combination of nanotechnology and chemotherapy has resulted in more effective drug design via the development of nanomaterial-based drug delivery systems (DDSs) for tumor targeting. Stimulus-responsive DDSs in response to internal or external signals can offer precisely controlled delivery of preloaded therapeutics. Among the various DDSs, the photo-triggered system improves the efficacy and safety of treatment through spatiotemporal manipulation of light. Additionally, pH-induced delivery is one of the most widely studied strategies for targeting the acidic micro-environment of solid tumors. Accordingly, in this review, we discuss representative strategies for designing DDSs using light as an exogenous signal or pH as an endogenous trigger.

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Wu, Kuo-Jen, Seongjin Yu, Jea-Young Lee, Barry Hoffer, and Yun Wang. "Improving Neurorepair in Stroke Brain Through Endogenous Neurogenesis-Enhancing Drugs." Cell Transplantation 26, no. 9 (September 2017): 1596–600. http://dx.doi.org/10.1177/0963689717721230.

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Stroke induces not only cell death but also neurorepair. De novo neurogenesis has been found in the subventricular zone of the adult mammalian brain days after stroke. Most of these newly generated cells die shortly after the insult. Recent studies have shown that pharmacological manipulation can improve the survival of endogenous neuroprogenitor cells and neural regeneration in stroke rats. As these drugs target the endogenous reparative processes that occur days after stroke, they may provide a prolonged window for stroke therapy. Here, we discuss endogenous neurogenesis-enhancing drugs and review the general status of stroke therapeutics in evaluating the field of pharmacotherapy for stroke.

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Kalra, Rajkumar Singh, Jaspreet Kaur Dhanjal, Mriganko Das, Birbal Singh, and Rajesh Naithani. "Cell Transdifferentiation and Reprogramming in Disease Modeling: Insights into the Neuronal and Cardiac Disease Models and Current Translational Strategies." Cells 10, no. 10 (September 27, 2021): 2558. http://dx.doi.org/10.3390/cells10102558.

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Cell transdifferentiation and reprogramming approaches in recent times have enabled the manipulation of cell fate by enrolling exogenous/artificial controls. The chemical/small molecule and regulatory components of transcription machinery serve as potential tools to execute cell transdifferentiation and have thereby uncovered new avenues for disease modeling and drug discovery. At the advanced stage, one can believe these methods can pave the way to develop efficient and sensitive gene therapy and regenerative medicine approaches. As we are beginning to learn about the utility of cell transdifferentiation and reprogramming, speculations about its applications in translational therapeutics are being largely anticipated. Although clinicians and researchers are endeavoring to scale these processes, we lack a comprehensive understanding of their mechanism(s), and the promises these offer for targeted and personalized therapeutics are scarce. In the present report, we endeavored to provide a detailed review of the original concept, methods and modalities enrolled in the field of cellular transdifferentiation and reprogramming. A special focus is given to the neuronal and cardiac systems/diseases towards scaling their utility in disease modeling and drug discovery.

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Foglizzo, Valentina, and Serena Marchiò. "Bacteriophages as Therapeutic and Diagnostic Vehicles in Cancer." Pharmaceuticals 14, no. 2 (February 17, 2021): 161. http://dx.doi.org/10.3390/ph14020161.

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Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production.

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