Article
Biochemistry & Molecular Biology
Ranjha Khan, Babak Oskouian, Joanna Y. Lee, Jeffrey B. Hodgin, Yingbao Yang, Gizachew Tassew, Julie D. Saba
Summary: Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a metabolic disorder caused by inactivating mutations in the SGPL1 gene. A study found that AAV-SPL gene therapy can prolong the survival of knockout mice and prevent or delay the onset of SPLIS phenotypes. The efficacy of a modified AAV-SPL 2.0, called AAV-SPL 2.0, was tested and showed equal or better results. However, improved kidney targeting may be necessary for optimal gene therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Nadja Meumann, Christian Schmithals, Leroy Elenschneider, Tanja Hansen, Asha Balakrishnan, Qingluan Hu, Sebastian Hook, Jessica Schmitz, Jan Hinrich Braesen, Ann-Christin Franke, Olaniyi Olarewaju, Christina Brandenberger, Steven R. Talbot, Josef Fangmann, Ulrich T. Hacker, Margarete Odenthal, Michael Ott, Albrecht Piiper, Hildegard Buening
Summary: In this study, we report on the natural preference of adeno-associated virus serotype 2 (AAV2) vectors for hepatocellular carcinoma (HCC), which is due to the improved intracellular processing of AAV2 vectors in HCC, resulting in more vector genomes serving as templates for transcription. Therefore, AAV2 vectors can be used to strengthen current therapeutic approaches or develop novel strategies for treating HCC.
Review
Neurosciences
Jing Wang, Mengna Zhu, Jingyi Sun, Lina Feng, Mingfeng Yang, Baoliang Sun, Leilei Mao
Summary: Stroke is associated with devastating clinical outcomes, and current treatment strategies are largely ineffective. Gene therapy using adeno-associated viruses (AAVs) as gene vectors has emerged as a promising approach for treating central nervous system diseases. This review provides an overview of the biological characteristics of AAV vectors and therapeutic advancements in preclinical models of ischemic stroke. It further investigates the potential of manipulating AAV vectors in preclinical applications, emphasizing the challenges and prospects in viral vector selection, drug delivery strategies, immune reactions, and clinical translation.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Review
Biotechnology & Applied Microbiology
Esther Rodriguez-Marquez, Nadja Meumann, Hildegard Buening
Summary: Capsid engineering is a promising strategy to improve the efficacy of AAV vector system in clinical application, by reducing vector dose, lowering the risk of immune responses, and decreasing manufacturing costs.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2021)
Article
Biochemistry & Molecular Biology
Lisa Strasser, Stefano Boi, Felipe Guapo, Nicholas Donohue, Niall Barron, Alana Rainbow-Fletcher, Jonathan Bones
Summary: AAV vectors are crucial for gene therapy, but manufacturing remains a challenge. This study investigated the host cell proteome of AAV5-producing cells, uncovering differential expression of proteins related to cellular metabolism, proliferation, cell death, as well as endocytosis and lysosomal degradation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Virology
Edward E. Large, Mark A. Silveria, Grant M. Zane, Onellah Weerakoon, Michael S. Chapman
Summary: Human gene therapy has advanced significantly from the concept in the 20th century to a reality in the 21st century, with recombinant Adeno-Associated Virus (rAAV) being a major gene therapy vector. Research is continuously working on improving the safety and efficacy of rAAV through various AAV capsid modification strategies, focusing on factors such as neutralizing antibodies and receptor binding to enhance transduction efficiency. Advances in understanding molecular interactions during rAAV cell entry, in combination with improved capsid modulation strategies, will lead to the design of safer and more efficient rAAV gene therapy vectors.
Article
Biotechnology & Applied Microbiology
Alejandro A. Schaffer, Dana A. Dominguez, Lesley M. Chapman, E. Michael Gertz, Anuradha Budhu, Marshonna Forgues, Jittiporn Chaisaingmongkol, Siritida Rabibhadana, Benjarath Pupacdi, Xiaolin Wu, Enkhjargal Bayarsaikhan, Curtis C. Harris, Mathuros Ruchirawat, Eytan Ruppin, Xin Wei Wang
Summary: The research revealed a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The presence of AAV segments and the positional bias of AAV integrations into the human genome complicate the analysis of the possible roles of AAV in liver cancer.
Article
Biochemical Research Methods
Logan Thrasher Collins, Selvarangan Ponnazhagan, David T. Curiel
Summary: Gene therapy has the potential to revolutionize disease treatment through direct genetic manipulation of cells. However, the high cost of Adeno-associated virus (AAV) gene therapy limits its accessibility, making it unaffordable for most patients. Therefore, efforts to decrease the production cost of AAVs using synthetic biology design have been proposed to make gene therapy more widely available.
ACS SYNTHETIC BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Jalish M. Riyad, Thomas Weber
Summary: Recombinant adeno-associated virus has become the most popular gene therapy vector in the last two decades, with higher doses increasing the risk of adverse events. FDA has recently approved AAV gene therapy for two rare genetic disorders, highlighting the need for better vectors to achieve therapeutic levels with lower doses. The review discusses cellular roadblocks that AAV must overcome and recent advancements in AAV biology that can improve vector performance for safer gene therapy.
Review
Biotechnology & Applied Microbiology
Pasquale Piccolo, Alessandro Rossi, Nicola Brunetti-Pierri
Summary: This review discusses the most relevant clinical applications and challenges of liver-directed gene-based approaches for therapy inborn errors of metabolism. Challenges and prospects of clinical gene therapy trials and preclinical studies with the greatest potential for clinical translation are presented.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2021)
Article
Biotechnology & Applied Microbiology
Shantoshini Dash, David M. Sharon, Alaka Mullick, Amine A. Kamen
Summary: This study reveals that only a small proportion of cells are capable of producing measurable levels of assembled AAV capsids despite high transfection efficiencies and nominal vector yields. Increasing the proportion of productive cells could significantly increase vector titer. The flow cytometry assay used in this study may serve as a useful metric for optimizing transfection-based AAV vector manufacturing platforms.
BIOTECHNOLOGY AND BIOENGINEERING
(2022)
Review
Oncology
Xin Xu, Wenli Chen, Wenjun Zhu, Jing Chen, Bin Ma, Jianxia Ding, Zaichuan Wang, Yifei Li, Yeming Wang, Xiaochun Zhang
Summary: Glioblastoma (GBM) is a common and malignant brain tumor with poor prognosis. Adeno-associated virus (AAV)-mediated gene therapy shows promise as a new treatment approach for GBM, with ongoing experimental trials and research on different injection methods.
CANCER CELL INTERNATIONAL
(2021)
Article
Endocrinology & Metabolism
Robert A. Kaiser, Nicholas D. Weber, Laia Trigueros-Motos, Kari L. Allen, Michael Martinez, William Cao, Caitlin J. VanLith, Lori G. Hillin, Anne Douar, Gloria Gonzalez-Aseguinolaza, Rafael Aldabe, Joseph B. Lillegard
Summary: The study demonstrates the therapeutic potential of AAV Anc80 in safely and durably curing PKU in a mouse model, showing significant reduction of phenylalanine levels and restoration of phenylalanine metabolism.
JOURNAL OF INHERITED METABOLIC DISEASE
(2021)
Review
Biotechnology & Applied Microbiology
Sha Sha, Andrew J. Maloney, Georgios Katsikis, Tam N. T. Nguyen, Caleb Neufeld, Jacqueline Wolfrum, Paul W. Barone, Stacy L. Springs, Scott R. Manalis, Anthony J. Sinskey, Richard D. Braatz
Summary: The article focuses on analyzing the bottlenecks in rAAV production during cell culture, comparing differences between wild-type and recombinant systems, and proposing future directions for improvement.
BIOTECHNOLOGY ADVANCES
(2021)
Article
Medicine, Research & Experimental
Yuqiu Wang, Chen Yang, Hanyang Hu, Chen Chen, Mengdi Yan, Feixiang Ling, Kathy Cheng Wang, Xintao Wang, Zhe Deng, Xinyue Zhou, Feixu Zhang, Sen Lin, Zengmin Du, Kai Zhao, Xiao Xiao
Summary: This study reports a novel AAV serotype, AAVzk2, which exhibits strong liver transduction and liver-specific gene delivery, similar to AAV8 and AAV9, with low immunoreactivity like AAV5. This provides a new therapeutic option for individuals who cannot be treated with AAV8 and AAV9.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Medicine, General & Internal
Roberta Romano, Francesca Cillo, Cristina Moracas, Laura Pignata, Chiara Nannola, Elisabetta Toriello, Antonio De Rosa, Emilia Cirillo, Emma Coppola, Giuliana Giardino, Nicola Brunetti-Pierri, Andrea Riccio, Claudio Pignata
Summary: The epigenome plays a crucial role in fine-tuning gene transcription by bridging environmental factors and the genome. It involves various intricate changes, such as DNA methylation, chromatin remodeling, histone modifications, and RNA processing, which regulate physiological processes in development, maturation, and maintenance of cellular identity and function. Recent studies on genome-wide DNA methylation data have shed new light on the potential contribution of epigenetics in the pathophysiology of the immune system and host defense. Understanding environment-genome interactions through the study of patients with mutations in genes encoding for epigenetic machinery has provided insights and potential therapeutic options.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Genetics & Heredity
Erik Rosenhahn, Thomas J. O'Brien, Maha S. Zaki, Ina Sorge, Dagmar Wieczorek, Kevin Rostasy, Antonio Vitobello, Sophie Nambot, Fowzan S. Alkuraya, Mais O. Hashem, Amal Alhashem, Brahim Tabarki, Abdullah S. Alamri, Ayat H. Al Safar, Dalal K. Bubshait, Nada F. Alahmady, Joseph G. Gleeson, Mohamed S. Abdel-Hamid, Nicole Lesko, Sofia Ygberg, Sandrina P. Correia, Anna Wredenberg, Shahryar Alavi, Seyed M. Seyedhassani, Mahya Ebrahimi Nasab, Haytham Hussien, Tarek E. Omar, Ines Harzallah, Renaud Touraine, Homa Tajsharghi, Heba Morsy, Henry Houlden, Mohammad Shahrooei, Maryam Ghavideldarestani, Ghada M. H. Abdel-Salam, Annalaura Torella, Mariateresa Zanobio, Gaetano Terrone, Nicola Brunetti-Pierri, Abdolmajid Omrani, Julia Hentschel, Johannes R. Lemke, Heinrich Sticht, Rami Abou Jamra, Andre E. X. Brown, Reza Maroofian, Konrad Platzer
Summary: This study identifies bi-allelic loss-of-function variants in the PPFIBP1 gene as a cause of severe neurodevelopmental disorder, characterized by early-onset epilepsy, microcephaly, and periventricular calcifications.
AMERICAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Gerarda Cappuccio, Margherita Lucia De Bernardi, Alessia Morlando, Cristina Peduto, Iris Scala, Michele Pinelli, Emanuele Bellacchio, Flavio Gioele Gallo, Adriano Magli, Carmen Plaitano, Mercedes Serrano, Leticia Pias, Jaume Catala, Merce Bolasell, Annalaura Torella, Vincenzo Nigro, Ginevra Zanni, Nicola Brunetti-Pierri
Summary: Hemizygous missense variants in the RPL10 gene cause an X-linked syndrome characterized by intellectual disability, autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies. This study identified a novel missense variant in RPL10 (p.(Arg32Leu)), which was found in four male children from three independent families. The variant is located in the 28S rRNA binding region and affects a conserved residue. All four boys with the variant showed retinal degeneration and postnatal microcephaly, in addition to features consistent with RPL10-related disorder. The findings suggest that retinopathy and postnatal microcephaly are clinical clues of RPL10-related disorder and may be specifically associated with the p.(Arg32Leu) variant.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Review
Hematology
Giovanni Di Minno, Giancarlo Castaman, Raimondo De Cristofaro, Nicola Brunetti-Pierri, Lucio Pastore, Giuseppe Castaldo, Ugo Trama, Matteo Di Minno
Summary: In individuals with severe hemophilia A, regular infusions of extended half-life factor VIII products or subcutaneous injections emicizumab are effective home treatments. Similarly, infusions of extended half-life factor IX products are recommended for individuals with severe hemophilia B. Gene therapy, currently being developed, offers a potential cure for hemophilia by correcting the hemostatic defect and providing sustained expression of clotting factors.
Article
Genetics & Heredity
Maimuna S. Paul, Anna R. Duncan, Casie A. Genetti, Hongling Pan, Adam Jackson, Patricia E. Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P. Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolini, Antonio Novelli, Ulrike Bluemlein, Tobias B. Haack, Wolfram Heinritz, Eva Matzker, Bader Alhaddad, Rami Abou Jamra, Tobias Bartolomaeus, Saber AlHamdan, Raphael Carapito, Bertrand Isidor, Seiamak Bahram, Alyssa Ritter, Kosuke Izumi, Ben Pode Shakked, Ortal Barel, Bruria Ben Zeev, Amber Begtrup, Deanna Alexis Carere, Sureni Mullegama, Timothy Blake Palculict, Daniel G. Calame, Katharina Schwan, Alicia R. P. Aycinena, Rasa Traberg, Sofia Douzgou, Harrison Pirt, Naila Ismayilova, Siddharth Banka, Hsiao-Tuan Chao, Pankaj B. Agrawal
Summary: Variants in the EIF4A2 gene cause a genetic neurodevelopmental syndrome characterized by global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies. These variants disrupt protein structure and result in both loss of function and gain of function mechanisms.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Medicine, Research & Experimental
Iolanda Boffa, Elena Polishchuk, Lucia De Stefano, Fabio Dell'Aquila, Edoardo Nusco, Elena Marrocco, Matteo Audano, Silvia Pedretti, Marianna Caterino, Ilaria Bellezza, Margherita Ruoppolo, Nico Mitro, Barbara Cellini, Alberto Auricchio, Nicola Brunetti-Pierri
Summary: GACR is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT). The current therapies are unsatisfactory and this study investigates the efficacy of liver-directed AAV-mediated gene therapy using an intravenously injected AAV8 vector expressing OAT. The results show that this gene therapy effectively reduces ornithine concentrations and improves retinal function and structure in mouse models of OAT deficiency.
EMBO MOLECULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Francesca Piceci-Sparascio, Lucia Micale, Barbara Torres, Valentina Guida, Federica Consoli, Isabella Torrente, Annamaria Onori, Emanuela Frustaci, Maria Cecilia D'Asdia, Francesco Petrizzelli, Laura Bernardini, Cecilia Mancini, Fiorenza Soli, Dario Cocciadiferro, Daniele Guadagnolo, Gioia Mastromoro, Carolina Putotto, Franco Fontana, Nicola Brunetti-Pierri, Antonio Novelli, Antonio Pizzuti, Bruno Marino, Maria Cristina Digilio, Tommaso Mazza, Bruno Dallapiccola, Victor Luis Ruiz-Perez, Marco Tartaglia, Marco Castori, Alessandro De Luca
Summary: Deleterious variants of the DYNC2H1 gene are associated with a wide range of skeletal ciliopathies. Targeted parallel sequencing was used to analyze 25 families with unresolved molecular diagnoses. Deleterious DYNC2H1 variants were identified in six sporadic patients and two monozygotic twins. The clinical phenotypes displayed a variety of skeletal ciliopathy disorders, including EvC, mixed ATD/EvC, and short rib-polydactyly/EvC.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Editorial Material
Genetics & Heredity
Jerry Vockley, Nicola Brunetti-Pierri, Wendy K. Chung, Angus J. Clarke, Nina Gold, Robert C. Green, Stephen Kagan, Tara Moroz, Christian P. Schaaf, Martin Schulz, Elfride De Baere
GENETICS IN MEDICINE
(2023)
Article
Endocrinology & Metabolism
Nicolina Cristina Sorrentino, Maximiliano Presa, Sergio Attanasio, Vincenzo Cacace, Martina Sofia, Aamir Zuberi, Jennifer Ryan, Somdatta Ray, Igor Petkovic, Karthikeyan Radhakrishnan, Lars Schlotawa, Andrea Ballabio, Cathleen Lutz, Nicola Brunetti-Pierri
Summary: Researchers have created mouse models carrying patient-based pathogenic variants to mimic multiple sulfatase deficiency (MSD), which can help in investigating the pathogenesis and treatments for this ultrarare lysosomal storage disorder.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Medicine, Research & Experimental
Lars Schlotawa, Karolina Tyka, Matthias Kettwig, Rebecca C. Ahrens-Nicklas, Matthias Baud, Tea Berulava, Nicola Brunetti-Pierri, Alyssa Gagne, Zackary M. Herbst, Jean A. Maguire, Jlenia Monfregula, Tonatiuh Pena, Karthikeyan Radhakrishnan, Sophie Schroeder, Elisa A. Waxman, Andrea Ballabio, Thomas Dierks, Andre Fischer, Deborah L. French, Michael H. Gelb, Jutta Gaertner
Summary: Multiple sulfatase deficiency (MSD) is caused by pathogenic variants in the SUMF1 gene, leading to dysfunction of the formylglycine-generating enzyme (FGE). Therapeutic options for MSD are limited, but treatment with retinoids tazarotene and bexarotene showed promising results in restoring sulfatase activities and normalizing lysosomal position and size. In addition, these retinoids increased stability of FGE variants, suggesting a potential therapeutic option for MSD patients using these drugs.
EMBO MOLECULAR MEDICINE
(2023)
Review
Endocrinology & Metabolism
Alessandro Rossi, Nicola Brunetti-Pierri
Summary: Current treatments for mucopolysaccharidoses (MPSs), including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), have limitations such as lack of effectiveness on brain and skeletal manifestations, lifelong injections, and high costs. Gene therapy in MPSs aims to achieve high levels of the therapeutic enzyme through gene-modified stem cells or viral vector infusion. This review discusses the recent clinical progress and various gene therapy approaches for MPSs.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Letter
Gastroenterology & Hepatology
Pasquale Piccolo, Nicola Brunetti-Pierri
HEPATOLOGY COMMUNICATIONS
(2022)
Meeting Abstract
Biotechnology & Applied Microbiology
Fabio Dell'Aquila, Roberto Di Cunto, Elena Marrocco, Simone Notaro, Iolanda Boffa, Nicola Brunetti-Pierri, Alberto Auricchio
Article
Genetics & Heredity
Michael A. Levy, Haley McConkey, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Robin S. Fletcher, Florian Cherik, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Ostergaard, Nathalie Ruiz Pallares, Maria Piccione, Simone Pizzi, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Raissa Relator, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos-Simarro, Josephine Schijns, Gabriella Maria Squeo, Miya St John, Christel Thauvin-Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti-Pierri, Philippe M. Campeau, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Kristin D. Kerrnohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman-Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic
Summary: Overlapping clinical phenotypes and complex genomic associations pose challenges in diagnosing and managing Mendelian disorders. This study identifies 19 new episignature disorders, in addition to 38 previously established episignatures, associated with a total of 65 genetic syndromes. The study demonstrates increasing resolution and specificity in identifying Mendelian episignatures at various molecular levels, and shows the development of accurate and disease-specific diagnostic classifiers. The findings expand the understanding of Mendelian conditions, improve clinical diagnostic capabilities, and offer potential reclassification of variants of unknown clinical significance.
HUMAN GENETICS AND GENOMICS ADVANCES
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Gerarda Cappuccio, Camilla Ceccatelli Berti, Enrico Baruffini, Jennifer Sullivan, Vandana Shashi, Tamison Jewett, Tara Stamper, Silvia Maitz, Francesco Canonico, Anya Revah-Politi, Gabriel S. Kupchik, Kwame Anyane-Yeboa, Vimla Aggarwal, Andreas Benneche, Eirik Bratland, Siren Berland, Felice D'Arco, Cesar Augusto Alves, Adeline Vanderver, Daniela Longo, Enrico Bertini, Annalaura Torella, Vincenzo Nigro, Alessandra D'Amico, Marjo S. van der Knaap, Paola Goffrini, Nicola Brunetti-Pierri
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)