Review
Immunology
Hildegund C. J. Ertl
Summary: Adeno-associated virus (AAV)-mediated gene transfer has shown benefits in treating patients with inherited diseases like hemophilia B, but challenges remain due to potential rejection of AAV-transduced cells. Immunosuppression may prevent rejection in some patients. CD8(+) T cells induced by AAV infections may recognize AAV vector's capsids and eliminate cells expressing degraded capsid antigens, or AAV vectors themselves may induce de novo T cell responses, particularly at high doses. This chapter discusses strategies to prevent activation of CD8(+) T cell responses to AAV infections and gene transfer.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biology
Michael Whitehead, Andrew Osborne, Patrick Yu-Wai-Man, Keith Martin
Summary: Viral vectors like AAV are effective for gene therapy, but pre-existing and induced NAbs in humans can limit their efficiency. Overcoming NAb responses remains a challenge, with successful translation of strategies into clinical practice still limited.
BIOLOGICAL REVIEWS
(2021)
Review
Pharmacology & Pharmacy
Duohao Ren, Sylvain Fisson, Deniz Dalkara, Divya Ail
Summary: Inherited retinal diseases are a major cause of blindness, and gene therapy using gene editing techniques like CRISPR-Cas9 shows promise for their treatment. However, ocular gene therapies can elicit immune responses that need to be managed to ensure safe and effective gene editing.
Article
Multidisciplinary Sciences
Chady H. Hakim, Sandeep R. P. Kumar, Dennis O. Perez-Lopez, Nalinda B. Wasala, Dong Zhang, Yongping Yue, James Teixeira, Xiufang Pan, Keqing Zhang, Emily D. Million, Christopher E. Nelson, Samantha Metzger, Jin Han, Jacqueline A. Louderman, Florian Schmidt, Feng Feng, Dirk Grimm, Bruce F. Smith, Gang Yao, N. Nora Yang, Charles A. Gersbach, Shi-jie Chen, Roland W. Herzog, Dongsheng Duan
Summary: The study investigates the immune responses induced by AAV-CRISPR therapy in canine models of DMD, indicating that the Cas9-specific T cell response may pose a critical barrier to treatment.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Ying Kai Chan, Sean K. Wang, Colin J. Chu, David A. Copland, Alexander J. Letizia, Helena Costa Verdera, Jessica J. Chiang, Meher Sethi, May K. Wang, William J. Neidermyer, Yingleong Chan, Elaine T. Lim, Amanda R. Graveline, Melinda Sanchez, Ryan F. Boyd, Thomas S. Vihtelic, Rolando Gian Carlo O. Inciong, Jared M. Slain, Priscilla J. Alphonse, Yunlu Xue, Lindsey R. Robinson-McCarthy, Jenny M. Tam, Maha H. Jabbar, Bhubanananda Sahu, Janelle F. Adeniran, Manish Muhuri, Phillip W. L. Tai, Jun Xie, Tyler B. Krause, Andyna Vernet, Matthew Pezone, Ru Xiao, Tina Liu, Wei Wang, Henry J. Kaplan, Guangping Gao, Andrew D. Dick, Federico Mingozzi, Maureen A. McCall, Constance L. Cepko, George M. Church
Summary: The study engineered AAV vectors by incorporating short DNA oligonucleotides to antagonize TLR9 activation, reducing innate immune responses and enhancing gene expression in clinically relevant animal models. The engineered vectors can avoid adverse reactions in some models, demonstrating a potential wider therapeutic window for AAV therapies.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Medicine, General & Internal
Eva Steinke, Olaf Sommerburg, Simon Y. Graeber, Cornelia Joachim, Christiane Labitzke, Gyde Nissen, Isabell Ricklefs, Isa Rudolf, Matthias V. Kopp, Anna-Maria Dittrich, Marcus A. Mall, Mirjam Stahl
Summary: This study is a prospective, longitudinal cohort study aimed at determining influencing factors of early cystic fibrosis (CF) lung disease through the combined analysis of clinical information and biomaterials. The primary endpoints are the lung clearance index and magnetic resonance imaging scores, while secondary endpoints include pulmonary exacerbations, infection with pro-inflammatory pathogens, and anthropometric data.
FRONTIERS IN MEDICINE
(2023)
Article
Respiratory System
Christina Thornton, Ranjani Somayaji, Angel Chu, Michael D. Parkins
Summary: Human papillomavirus (HPV) is a major risk factor for cervical cancer, and transplant recipients have a higher risk of HPV complications. A retrospective study on adult female cystic fibrosis (CF) lung transplant recipients found that 35.3% had abnormal pap smear results, including refractory anogenital warts, vulvectomy, and cervical cancer. The study also revealed that lung transplant recipients had a higher likelihood of cervical dysplasia compared to the control group, emphasizing the importance of HPV vaccination to prevent future morbidity and mortality.
Review
Biotechnology & Applied Microbiology
Helena Costa-Verdera, Carmen Unzu, Erika Valeri, Sahil Adriouch, Gloria Gonzalez Aseguinolaza, Federico Mingozzi, Anna Kajaste-Rudnitski
Summary: As the clinical experience in AAV vector-based gene therapies grows, there is a need to better understand and control the host immune responses. Our current understanding of the immune responses to AAV gene therapies is limited, which is further hindered by the lack of replication of clinical findings in preclinical animal models.
HUMAN GENE THERAPY
(2023)
Article
Immunology
Bradley A. Hamilton, J. Fraser Wright
Summary: This article discusses the host immune responses that limit durable therapeutic gene expression in AAV-based human gene therapies. A strategy of removing pathogen-associated molecular patterns in AAV vector genomes to overcome immunological barriers is proposed.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Endocrinology & Metabolism
Lise Coderre, Lyna Debieche, Joelle Plourde, Remi Rabasa-Lhoret, Sylvie Lesage
Summary: Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis patients, with a prevalence of over 50% in adults. The etiology of CFRD is not fully understood, but research suggests it may result from beta-cell extrinsic factors. Inflammation and ductal cells near beta-cells could play a role in CFRD development.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Medicine, Research & Experimental
Divya Ail, Duohao Ren, Elena Brazhnikova, Celine Nouvel-Jaillard, Stephane Bertin, Seyed Bagher Mirashrafi, Sylvain Fisson, Deniz Dalkara
Summary: This study investigates the potential inflammatory responses in AAV-mediated retinal gene therapy and the correlation between pre-existing serum antibodies and clinical outcomes. The results show a dose-dependent increase in antibodies after injection, and a correlation between serum antibody levels, inflammation, and transgene expression.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2022)
Article
Psychology, Multidisciplinary
Deborah Friedman, Maysa M. Kaskas, Alexandra L. Quittner, Beth A. Smith, Anna M. Georgiopoulos
Summary: Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety. This study developed a CBT-based intervention tailored to CF-specific needs, with positive feedback from patients.
FRONTIERS IN PSYCHOLOGY
(2022)
Article
Cell Biology
M. Gordon Joyce, Hannah A. D. King, Ines Elakhal-Naouar, Aslaa Ahmed, Kristina K. Peachman, Camila Macedo Cincotta, Caroline Subra, Rita E. Chen, Paul Thomas, Wei-Hung Chen, Rajeshwer S. Sankhala, Agnes Hajduczki, Elizabeth J. Martinez, Caroline E. Peterson, William C. Chang, Misook Choe, Clayton Smith, Parker J. Lee, Jarrett A. Headley, Mekdi G. Taddese, Hanne A. Elyard, Anthony Cook, Alexander Anderson, Kathryn McGuckin Wuertz, Ming Dong, Isabella Swafford, James Brett Case, Jeffrey R. Currier, Kerri G. Lal, Sebastian Molnar, Manoj S. Nair, Vincent Dussupt, Sharon P. Daye, Xiankun Zeng, Erica K. Barkei, Hilary M. Staples, Kendra Alfson, Ricardo Carrion, Shelly J. Krebs, Dominic Paquin-Proulx, Nicos Karasavva, Victoria R. Polonis, Linda L. Jagodzinski, Mihret F. Amare, Sandhya Vasan, Paul T. Scott, Yaoxing Huang, David D. Ho, Natalia de Val, Michael S. Diamond, Mark G. Lewis, Mangala Rao, Gary R. Matyas, Gregory D. Gromowski, Sheila A. Peel, Nelson L. Michael, Diane L. Bolton, Kayvon Modjarrad
Summary: This study developed an adjuvanted SARS-CoV-2 vaccine, which was found to induce strong immune responses and effectively eliminate the virus when challenged with high doses in nonhuman primates.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Genetics & Heredity
Panayiotis K. Yiallouros, Andreas M. Matthaiou, Pinelopi Anagnostopoulou, Panayiotis Kouis, Malgorzata Libik, Tonia Adamidi, Adonis Eleftheriou, Artemios Demetriou, Phivos Ioannou, George A. Tanteles, Constantina Costi, Pavlos Fanis, Milan Macek, Vassos Neocleous, Leonidas A. Phylactou
Summary: In Cyprus, where specialized clinical care for cystic fibrosis has been provided since the 1990s, a national CF patient registry was recently established to systematically record patients' data. This study presented data on CF patients in the country, showing common initial symptoms, high sweat chloride levels in diagnosed patients, and the prevalence of the F508del mutation, as well as unique genotypic profiles.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Health Care Sciences & Services
Tomasz Hildebrandt, Elzbieta Swietochowska, Agata Trzcionka, Anna Zawilska, Henryk Mazurek, Dagmara Maczkowiak, Mansur Rahnama, Marta Tanasiewicz
Summary: This study assessed the oral hygiene status of adult cystic fibrosis patients and found that their oral hygiene was satisfactory. However, professional preventive treatments were needed.
Article
Surgery
Amanda Fazzalari, Giacomo Basadonna, Alper Kucukural, Kahraman Tanriverdi, Milka Koupenova, Natalie Pozzi, Jahnavi Kakuturu, Ann-Kristin U. Friedrich, Ron Korstanje, Nicholas Fowler, Jerrold L. Belant, Dean E. Beyer, Marjory B. Brooks, Eric W. Dickson, Meghan Blackwood, Chris Mueller, J. Alexander Palesty, Jane E. Freedman, Mitchell A. Cahan
Summary: Differences in microRNA expression were observed in the plasma of hibernating black bears, with three microRNAs potentially regulating antithrombin gene expression and contributing to their hemostatic ability during hibernation.
JOURNAL OF SURGICAL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Pasquale Piccolo, Rosa Ferriero, Anna Barbato, Sergio Attanasio, Marcello Monti, Claudia Perna, Florie Borel, Patrizia Annunziata, Annamaria Carissimo, Rossella De Cegli, Luca Quagliata, Luigi M. Terracciano, Chantal Housset, Jeffrey H. Teckman, Christian Mueller, Nicola Brunetti-Pierri
Summary: AAT deficiency is caused by pathogenic variants in the SERPINA1 gene, with the Z allele encoding for Z alpha 1-antitrypsin leading to hepatotoxic polymers. The up-regulation of miR-34b/c in PiZ mouse livers is correlated to intrahepatic ATZ, and its expression is dependent on JNK phosphorylation on Ser574. Deletion of miR-34b/c in PiZ mice results in early liver fibrosis and increased signaling of platelet-derived growth factor.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Medicine, Research & Experimental
Lena Ostermann, Regina Maus, Jennifer Stolper, Lisanne Schutte, Konstantina Katsarou, Srinu Tumpara, Andreas Pich, Christian Mueller, Sabina Janciauskiene, Tobias Welte, Ulrich A. Maus
Summary: The study found that in AAT-deficient mice, NE can degrade lung SP-A and SP-D, affecting lung protective immunity. Treatment with human AAT or the NE-specific inhibitor Sivelestat can protect collectins from degradation and reduce bacterial loads in S. pneumoniae-infected AAT-KO mice.
Article
Biochemistry & Molecular Biology
Wanru Qin, Guangchao Xu, Phillip W. L. Tai, Chunmei Wang, Li Luo, Chengjian Li, Xun Hu, Jianxin Xue, You Lu, Qiao Zhou, Qiang Wei, Tianfu Wen, Jiankun Hu, Yuanyuan Xiao, Li Yang, Weimin Li, Terence R. Flotte, Yuquan Wei, Guangping Gao
Summary: The study revealed that over 80% of patients across nine types of carcinoma had AAV present in their bodies, with AAV genomes equally abundant in tumors and adjacent normal tissues, but lacking clonality.
Article
Neurosciences
Owen M. Peters, Alexandra Weiss, Jake Metterville, Lina Song, Robert Logan, Gaynor A. Smith, Michael A. Schwarzschild, Christian Mueller, Robert H. Brown, Marc Freeman
Summary: Parkinson's disease is a neurodegenerative movement disorder linked to profound loss of dopaminergic neurons in the basal ganglia. Studies suggest that Sarm1 contributes to degeneration of dopaminergic projections in the nigrostriatal tract, but its role may vary in different models of PD.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Multidisciplinary Sciences
Tobias Deuse, Grigol Tediashvili, Xiaomeng Hu, Alessia Gravina, Annika Tamenang, Dong Wang, Andrew Connolly, Christian Mueller, Benat Mallavia, Mark R. Looney, Malik Alawi, Lewis L. Lanier, Sonja Schrepfer
Summary: This study demonstrates that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in fully allogeneic recipients, improving conditions like critical limb ischemia, genetic A1AT deficiency, and emphysematous lung disease in mouse models. Furthermore, a mixture of endothelial cells and cardiomyocytes engrafted in infarcted mouse hearts, leading to an improvement in invasive hemodynamic heart failure parameters. The study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Pharmacology & Pharmacy
Terence R. Flotte, Dominic J. Gessler
Summary: There are over 7,000 individually rare diseases that collectively affect millions of people globally. Neurologic single-gene disorders are particularly common among them. Recent advancements in recombinant adeno-associated virus vectors have paved the way for gene therapies for rare neurologic diseases, including FDA-approved treatments for inherited retinal dystrophy and spinal muscular atrophy. Further development of gene editing technologies holds the promise of expanding innovative therapies to benefit more patients with these disorders.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Terence R. Flotte, Oguz Cataltepe, Ajit Puri, Ana Rita Batista, Richard Moser, Diane McKenna-Yasek, Catherine Douthwright, Gwladys Gernoux, Meghan Blackwood, Christian Mueller, Phillip W. L. Tai, Xuntian Jiang, Scot Bateman, Spiro G. Spanakis, Julia Parzych, Allison M. Keeler, Aly Abayazeed, Saurabh Rohatgi, Laura Gibson, Robert Finberg, Bruce A. Barton, Zeynep Vardar, Mohammed Salman Shazeeb, Matthew Gounis, Cynthia J. Tifft, Florian S. Eichler, Robert H. Brown, Douglas R. Martin, Heather L. Gray-Edwards, Miguel Sena-Esteves
Summary: This study presents the results of AAV gene therapy in two patients with infantile TSD. The treatment was well tolerated without vector-related adverse events, and demonstrated an increase and stability of HexA activity in the cerebrospinal fluid. One patient showed disease stabilization, while the other experienced disease progression after treatment.
Article
Microbiology
Mario Meza-Segura, James R. Birtley, Ana Maldonado-Contreras, Christian Mueller, Karl J. Simin, Lawrence J. Stern, Beth A. McCormick
Summary: Shigella spp. are highly adapted pathogens that cause bacillary dysentery by disrupting the intestinal epithelial barrier, with SepA releasing a neutrophil chemoattractant that promotes Shigella invasion.
Review
Biotechnology & Applied Microbiology
Beverly L. Davidson, Guangping Gao, Elizabeth Berry-Kravis, Allison M. Bradbury, Carsten Bonnemann, Joseph D. Buxbaum, Gavin R. Corcoran, Steven J. Gray, Heather Gray-Edwards, Robin J. Kleiman, Adam J. Shaywitz, Dan Wang, Huda Y. Zoghbi, Terence R. Flotte, Sitra Tauscher-Wisniewski, Cynthia J. Tifft, Mustafa Sahin
Summary: The review summarizes the discussions and presentations of a workshop sponsored by the National Institute of Mental Health, focusing on gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders. It highlights the potential of precision medicine approaches in treating these disorders.
Article
Multidisciplinary Sciences
Haiping Ke, Kevin P. Guay, Terence R. Flotte, Lila M. Gierasch, Anne Gershenson, Daniel N. Hebert
Summary: This study analyzed the production efficiency of α1-antitrypsin (AAT) in Chinese hamster ovary cells and myoblasts, and compared it to liver hepatocytes. The study found that AAT secretion and maturation were most efficient in hepatocytes, while myoblasts had the lowest expression efficiency. Treatment with a specific drug significantly enhanced the secretion of active AAT in myoblasts. These findings may have implications for enhancing the efficacy of gene therapy approaches for AAT and the production of proteins from mRNA vaccines.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Oncology
Motahareh Arjomandnejad, Ishani Dasgupta, Terence R. Flotte, Allison M. Keeler
Summary: Recombinant adeno-associated viruses (AAVs) have shown promise as gene delivery vehicles, but immune responses against the AAV vector and transgene have limited their widespread application. Factors such as vector design, dose, and route of administration influence the immunogenicity of AAVs. Innate immune sensing and subsequent adaptive immune response contribute to the specific reactions against AAV vectors. This review discusses the challenges and potential strategies to mitigate immune responses, thereby enhancing the therapeutic potential of AAV gene therapy.
Review
Biotechnology & Applied Microbiology
Debora Pires Ferreira, Alisha M. Gruntman, Terence R. Flotte
Summary: Since the early 1990s, altering the human genetic code has been explored as a definitive treatment for monogenic and acquired diseases. Alpha-1 antitrypsin deficiency (AATD) is one such disease that has been targeted for gene therapy due to its single gene mutation. AATD gene therapy faces challenges in achieving safe and effective expression of the AAT protein.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Editorial Material
Biotechnology & Applied Microbiology
Cheryl L. McDonald, Pankaj Qasba, Daniel G. Anderson, Gang Bao, Richard A. Colvin, Donald B. Kohn, Punam Malik, Michael J. Mitchell, William T. Pu, David J. Rawlings, David A. Williams, Terence R. Flotte
HUMAN GENE THERAPY
(2023)
Editorial Material
Biotechnology & Applied Microbiology
Ying Kai Chan, Terence R. Flotte