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Article ; Online: Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China.

Kruse, Robert L

2020 Volume 9, Page(s) 72

Abstract: A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be ... ...

Abstract	A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Antibodies, Neutralizing/therapeutic use ; Betacoronavirus/drug effects ; China/epidemiology ; Compassionate Use Trials ; Coronavirus Infections/drug therapy ; Disease Outbreaks ; Drug Repositioning ; Humans ; Oligonucleotides/therapeutic use ; Peptidyl-Dipeptidase A/drug effects ; Pneumonia, Viral/drug therapy
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Oligonucleotides ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; angiotensin converting enzyme 2 (EC 3.4.17.-)
Keywords	covid19
Language	English
Publishing date	2020-01-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402 ; 2046-1402
ISSN (online)	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.22211.2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: How to Embrace Gene Therapy in Gastroenterology.

Kruse, Robert L / Huang, Yuting / Kumbhari, Vivek

Gastroenterology

2022 Volume 162, Issue 4, Page(s) 1019–1023

MeSH term(s)	Gastroenterology ; Genetic Therapy ; Humans
Language	English
Publishing date	2022-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2022.01.026
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Article: Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

Kruse, Robert L

F1000Res

Abstract	A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32117569
Database	COVID19

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Article ; Online: Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China [version 2; peer review

Robert L. Kruse

F1000Research, Vol

2 approved]

2020 Volume 9

Abstract	A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain (ACE2-Fc), providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The ACE2-Fc therapy would also supplement decreased ACE2 levels in the lungs during infection, thereby directly treating acute respiratory distress pathophysiology as a third mechanism of action. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
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Article: Wilson Disease: Update on Pathophysiology and Treatment.

Dev, Som / Kruse, Robert L / Hamilton, James P / Lutsenko, Svetlana

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 871877

Abstract: Wilson disease (WD) is a potentially fatal genetic disorder with a broad spectrum of phenotypic presentations. Inactivation of the copper (Cu) transporter ATP7B and Cu overload in tissues, especially in the liver, are established causes of WD. However, ... ...

Abstract	Wilson disease (WD) is a potentially fatal genetic disorder with a broad spectrum of phenotypic presentations. Inactivation of the copper (Cu) transporter ATP7B and Cu overload in tissues, especially in the liver, are established causes of WD. However, neither specific ATP7B mutations nor hepatic Cu levels, alone, explain the diverse clinical presentations of WD. Recently, the new molecular details of WD progression and metabolic signatures of WD phenotypes began to emerge. Studies in WD patients and animal models revealed the contributions of non-parenchymal liver cells and extrahepatic tissues to the liver phenotype, and pointed to dysregulation of nuclear receptors (NR), epigenetic modifications, and mitochondria dysfunction as important hallmarks of WD pathogenesis. This review summarizes recent advances in the characterization of WD pathophysiology and discusses emerging targets for improving WD diagnosis and treatment.
Language	English
Publishing date	2022-05-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.871877
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Article ; Online: Wilson Disease

Som Dev / Robert L. Kruse / James P. Hamilton / Svetlana Lutsenko

Frontiers in Cell and Developmental Biology, Vol

Update on Pathophysiology and Treatment

2022 Volume 10

Abstract	Wilson disease (WD) is a potentially fatal genetic disorder with a broad spectrum of phenotypic presentations. Inactivation of the copper (Cu) transporter ATP7B and Cu overload in tissues, especially in the liver, are established causes of WD. However, neither specific ATP7B mutations nor hepatic Cu levels, alone, explain the diverse clinical presentations of WD. Recently, the new molecular details of WD progression and metabolic signatures of WD phenotypes began to emerge. Studies in WD patients and animal models revealed the contributions of non-parenchymal liver cells and extrahepatic tissues to the liver phenotype, and pointed to dysregulation of nuclear receptors (NR), epigenetic modifications, and mitochondria dysfunction as important hallmarks of WD pathogenesis. This review summarizes recent advances in the characterization of WD pathophysiology and discusses emerging targets for improving WD diagnosis and treatment.
Keywords	copper ; liver ; Wilson disease ; ATP7B ; nuclear receptor ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Cre/LoxP-HBV plasmids generating recombinant covalently closed circular DNA genome upon transfection.

Kruse, Robert L / Legras, Xavier / Barzi, Mercedes

Virus research

2020 Volume 292, Page(s) 198224

Abstract: New therapies against hepatitis B virus (HBV) require the elimination of covalently closed circular DNA (cccDNA), the episomal HBV genome. HBV plasmids containing an overlength 1.3-mer genome and bacterial backbone (pHBV1.3) are used in many different ... ...

Abstract	New therapies against hepatitis B virus (HBV) require the elimination of covalently closed circular DNA (cccDNA), the episomal HBV genome. HBV plasmids containing an overlength 1.3-mer genome and bacterial backbone (pHBV1.3) are used in many different models, but do not replicate the unique features of cccDNA. Since the stable cccDNA pool is a barrier to HBV eradication in patients, we developed a recombinant circular HBV genome (rcccDNA) to mimic the cccDNA using Cre/LoxP technology. We validated four LoxP insertion sites into the HBV genome using hydrodynamic tail vein injection into murine liver, demonstrating high levels of HBV surface antigen (HBsAg) and HBV DNA expression with rcccDNA formation. HBsAg expression from rcccDNA was >30,000 ng/mL over 78 days, while HBsAg-expression from pHBV1.3 plasmid DNA declined from 2753 ng/mL to 131 ng/mL over that time in immunodeficient mice (P < 0.001), reflective of plasmid DNA silencing. We then cloned Cre-recombinase in cis on the LoxP-HBV plasmids, achieving plasmid stability in bacteria with intron insertion into Cre and demonstrating rcccDNA formation after transfection in vitro and in vivo. These cis-Cre/LoxP-HBV plasmids were then used to create HBx-mutant and GFP reporter plasmids to further probe cccDNA biology and antiviral strategies against cccDNA. Overall, we believe these auto-generating rcccDNA plasmids will be of great value to model cccDNA for testing new therapies against HBV infection.
MeSH term(s)	DNA, Circular/chemistry ; DNA, Circular/genetics ; DNA, Recombinant/chemistry ; DNA, Recombinant/genetics ; DNA, Viral/chemistry ; DNA, Viral/genetics ; Genetic Engineering/methods ; Genome, Viral ; Hepatitis B/virology ; Hepatitis B Surface Antigens/genetics ; Hepatitis B Surface Antigens/metabolism ; Hepatitis B virus/chemistry ; Hepatitis B virus/genetics ; Hepatitis B virus/metabolism ; Humans ; Integrases/metabolism ; Plasmids/genetics ; Plasmids/metabolism ; Transfection
Chemical Substances	DNA, Circular ; DNA, Recombinant ; DNA, Viral ; Hepatitis B Surface Antigens ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2020-11-06
Publishing country	Netherlands
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.198224
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Article ; Online: Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities.

Shum, Thomas / Kruse, Robert L / Rooney, Cliona M

Expert opinion on biological therapy

2018 Volume 18, Issue 6, Page(s) 653–664

Abstract: Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma ... ...

Abstract	Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.
MeSH term(s)	Animals ; Cell Engineering/methods ; Combined Modality Therapy/methods ; Cytokines/genetics ; Cytokines/metabolism ; Genetic Therapy/methods ; Humans ; Immunologic Factors/genetics ; Immunologic Factors/metabolism ; Immunotherapy/methods ; Immunotherapy, Adoptive/methods ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Signal Transduction/genetics ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Cytokines ; Immunologic Factors ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2018-05-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1080/14712598.2018.1473368
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Article ; Online: Exploring a case for education about sexual and gender minorities in postgraduate emergency medicine training: forming recommendations for change.

Burcheri, Adam / Coutin, Alexandre / Bigham, Blair L / Kruse, Michael I / Lien, Kelly / Lim, Rodrick / MacCormick, Hilary / Morris, Judy / Ng, Victor / Primiani, Nadia / Odorizzi, Scott / Poirier, Vincent / Upadhye, Suneel / Primavesi, Robert

Postgraduate medicine

2023 Volume 135, Issue 6, Page(s) 623–632

Abstract: Social medicine and health advocacy curricula are known to be uncommon in postgraduate medical education. As justice movements work to unveil the systemic barriers experienced by sexual and gender minority (SGM) populations, it is imperative that the ... ...

Abstract	Social medicine and health advocacy curricula are known to be uncommon in postgraduate medical education. As justice movements work to unveil the systemic barriers experienced by sexual and gender minority (SGM) populations, it is imperative that the emergency medicine (EM) community progress in its efforts to provide equitable, accessible, and competent care for these vulnerable groups. Given the paucity of literature on this subject in the context of EM in Canada, this commentary borrows evidence from other specialties across North America. Trainees across specialties and of all stages are caring for an increasing number of SGM patients. Lack of education at all levels of training is identified as a significant barrier to adequately caring for these populations, thereby precipitating significant health disparities. Cultural competency is often mistakenly attributed to a willingness to treat rather than the provision of quality care. However, positive attitudes do not necessarily correlate with trainee knowledge. Barriers to creating and implementing culturally competent curricula are plentiful, yet facilitating policies and resources are rare. While international bodies continuously publish position statements and calls to action, concrete change is seldom made. The scarcity of SGM curricula can be attributed to the universal absence of formal acknowledgment of SGM health as a required competency by accreditation boards and professional membership associations. This commentary synthesizes hand-picked literature in an attempt to inform healthcare professionals on their journey toward developing culturally competent postgraduate medical education. By thematically organizing evidence into a stepwise approach, the goal of this article is to borrow ideas across medical and surgical specialties to inform the creation of recommendations and make a case for an SGM curriculum for EM programs in Canada.
MeSH term(s)	Humans ; Sexual and Gender Minorities ; Curriculum ; Health Personnel ; Education, Medical ; Emergency Medicine
Language	English
Publishing date	2023-06-15
Publishing country	England
Document type	Journal Article
ZDB-ID	410138-8
ISSN	1941-9260 ; 0032-5481
ISSN (online)	1941-9260
ISSN	0032-5481
DOI	10.1080/00325481.2023.2225329
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Article ; Online: High cell density cultivation enables efficient and sustainable recombinant polyamine production in the microalga Chlamydomonas reinhardtii.

Freudenberg, Robert A / Baier, Thomas / Einhaus, Alexander / Wobbe, Lutz / Kruse, Olaf

Bioresource technology

2020 Volume 323, Page(s) 124542

Abstract: ... and cell count (20 g/L biomass dry weight, ~2·10 ...

Abstract	Modern chemical industry calls for new resource-efficient and sustainable value chains for production of key base chemicals such as polyamines. The green microalga Chlamydomonas reinhardtii offers great potential as an innovative green-cell factory by combining fast and inexpensive, phototrophic growth with mature genetic engineering. Here, overexpression of recombinant lysine decarboxylases in C. reinhardtii enabled the robust accumulation of the non-native polyamine cadaverine, which serves as building block for bio-polyamides. The issue of low cell densities, limiting most microalgal cultivation processes was resolved by systematically optimizing cultivation parameters. A new, easy-to-apply and fully phototrophic medium enables high cell density cultivations of C. reinhardtii with a 6-fold increase in biomass and cell count (20 g/L biomass dry weight, ~2·10
MeSH term(s)	Biomass ; Cell Count ; Chlamydomonas reinhardtii/genetics ; Microalgae ; Photobioreactors ; Polyamines
Chemical Substances	Polyamines
Language	English
Publishing date	2020-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1065195-0
ISSN	1873-2976 ; 0960-8524
ISSN (online)	1873-2976
ISSN	0960-8524
DOI	10.1016/j.biortech.2020.124542
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