scholarly journals Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety

2022 ◽  
Vol 23 (2) ◽  
pp. 819
Author(s):  
Sherif G. Ahmed ◽  
Casey A. Maguire ◽  
Shiliang Alice Cao ◽  
Gary J. Brenner
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Viral Vector ◽  
Cranial Nerves ◽  
Adaptor Protein ◽  
Primary Treatment ◽  
Motor Dysfunction ◽  
Therapy Strategy ◽  
Virus Serotype ◽  
Immunocompetent Mice

Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.

scholarly journals Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease

2020 ◽  
Vol 91 (11) ◽  
pp. 1210-1218 ◽  
Author(s):  
R Mark Richardson ◽  
Krystof S Bankiewicz ◽  
Chadwick W Christine ◽  
Amber D Van Laar ◽  
Robert E Gross ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Viral Vector ◽  
Data Driven ◽  
Surgical Approaches ◽  
Acid Decarboxylase ◽  
Projection Neurons ◽  
Virus Serotype ◽  
Vector Delivery

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

scholarly journals Gene therapy for hemophilia: what does the future hold?

2018 ◽  
Vol 9 (9) ◽  
pp. 273-293 ◽  
Author(s):  
Bhavya S. Doshi ◽  
Valder R. Arruda
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Viral Vector ◽  
Young Patients ◽  
Clotting Factors ◽  
Liver Transaminase ◽  
Long Term Follow Up ◽  
Recent Phase ◽  
Universal Applicability

Recent phase I/II adeno-associated viral vector-mediated gene therapy clinical trials have reported remarkable success in ameliorating disease phenotype in hemophilia A and B. These trials, which highlight the challenges overcome through decades of preclinical and first in human clinical studies, have generated considerable excitement for patients and caregivers alike. Optimization of vector and transgene expression has significantly improved the ability to achieve therapeutic factor levels in these subjects. Long-term follow-up studies will guide standardization of the approach with respect to the combination of serotype, promoter, dose, and manufacturing processes and inform safety for inclusion of young patients. Certain limitations preclude universal applicability of gene therapy, including transient liver transaminase elevations due to the immune responses to vector capsids or as yet undefined mechanisms, underlying liver disease from iatrogenic viral hepatitis, and neutralizing antibodies to clotting factors. Integrating vectors show promising preclinical results, but manufacturing and safety concerns still remain. The prospect of gene editing for correction of the underlying mutation is on the horizon with considerable potential. Herein, we review the advances and limitations that have resulted in these recent successful clinical trials and outline avenues that will allow for broader applicability of gene therapy.

scholarly journals The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

2019 ◽  
Vol 9 (2) ◽  
pp. 32 ◽  
Author(s):  
David Hampson ◽  
Alexander Hooper ◽  
Yosuke Niibori
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Fragile X Syndrome ◽  
Viral Vectors ◽  
Viral Vector ◽  
Fragile X ◽  
Animal Models Of Disease ◽  
Key Issues ◽  
Full Correction ◽  
Models Of Disease

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Here we provide a backdrop of recent advances in AAV gene therapy as applied to central nervous system disorders, outline the salient features of the fragile X studies, and discuss several key issues for moving forward. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome.

scholarly journals Engineered T cell therapies

2015 ◽  
Vol 17 ◽  
Author(s):  
Anne-Christine Field ◽  
Waseem Qasim
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
T Cell ◽  
Viral Vector ◽  
Ex Vivo ◽  
Immune Disorders ◽  
Clinical Experiences ◽  
Cell Therapies ◽  
Cell Gene

Alongside advancements in gene therapy for inherited immune disorders, the need for effective alternative therapeutic options for other conditions has resulted in an expansion in the field of research for T cell gene therapy. T cells are easily obtained and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to viral vector-mediated introduction of transgenes. Pioneering clinical trials targeting cancers and infectious diseases have provided safety and feasibility data and important information about persistence of engineered cells in vivo. Here, we review clinical experiences with γ-retroviral and lentiviral vectors and consider the potential of integrating transposon-based vectors as well as specific genome editing with designer nucleases in engineered T cell therapies.

Cardiac disease: Current approaches to gene therapy

2020 ◽  
pp. 62-75
Author(s):  
Reyad ul-ferdous ◽  
◽  
Shofiul Azam ◽  
◽  
◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Cardiac Disease ◽  
Target Genes ◽  
Viral Vector ◽  
Delivery Methods ◽  
Gene Therapies ◽  
Inherited Cardiomyopathies

Background: Last decade over the world, the cardiac disease becomes a leading cause of death. Gene-based therapies become a promising treatment for patients affected by cardiovascular diseases, such as myocardial infarction (MI), arteriosclerosis, heart failure and so on, but also underline the require for reproducible results in preclinical and clinical studies for efficacy and safety. Aim: This book chapter describes the current research prospect of gene therapy for cardiac disease. We focus on the various models to deliver genes using viral, non-viral vector, delivery methods, targets gene, recent clinical trials, inherited cardiomyopathies target genes and Present advances of CRISPR/Cas 9 for cardiovascular gene therapy. We recapitulate some challenges that require being overcome, future directions of gene therapies for cardiac disease. Materials and Methods: All required information regards Lef-7 was generated by exploring the internet search engine like as (PubMed, Wiley, ScienceDirect, CNKI, ACS, Google Scholar, Web of Science, SciFinder, and Baidu Scholar) and libraries. Results: In this book chapter, we focus on the present prospect of gene targets, gene delivery methods, and efficient vector to deliver gene, targets gene, recent clinical trials, inherited cardiomyopathies target genes and present advances of CRISPR/Cas 9 technology for the treatment of cardiac disease using gene therapy. Recent clinical trials require modifying vectors and gene delivery approaches to achieve effective results for cardiac gene therapy. Conclusion: In this book chapter, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.

scholarly journals GENE THERAPY FOR OBSTETRIC CONDITIONS

2014 ◽  
Vol 25 (3-4) ◽  
pp. 147-177
Author(s):  
REBECCA N. SPENCER ◽  
DAVID J. CARR ◽  
ANNA L. DAVID
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Lipoprotein Lipase ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Nasopharyngeal Cancer ◽  
New Paradigm ◽  
Gene Therapies

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy.

Viral Vector Delivery of DREADDs for CNS Therapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Ceri A. Pickering ◽  
Nicholas D. Mazarakis
Keyword(s):  
Gene Therapy ◽  
Viral Vector ◽  
Designer Drugs ◽  
Target Cells ◽  
Delivery Methods ◽  
Therapy Strategy ◽  
Synthetic Ligand ◽  
The Central Nervous System ◽  
Gene Therapy Strategy ◽  
Vector Delivery

: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are genetically modified G-protein-coupled receptors (GPCRs), which can be activated by a synthetic ligand that is otherwise inert at endogenous receptors. DREADDs can be expressed in cells in the central nervous system (CNS) and subsequently offer the opportunity for remote and reversible silencing or activation of the target cells when the synthetic ligand is systemically administered. In neuroscience, DREADDs have thus far shown to be useful tools for several areas of research. Furthermore, they offer considerable potential for use as a gene therapy strategy for neurological disorders. However, in order to design a DREADD-based gene therapy, it is necessary to first evaluate the viral vector delivery methods utilised to deliver these chemogenetic tools in the literature. This review evaluates each of the prominent strategies currently utilised for DREADD delivery, discussing their respective advantages and limitations. It focuses on Adeno-Associated Virus (AAV)- and lentivirus-based systems, and the manipulation of these through cell-type specific promoters and pseudotyping. Furthermore, we address how virally mediated DREADD delivery could be improved in order to make it a viable gene therapy strategy and thus expand its translational potential.

scholarly journals Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
Aristide Merola ◽  
Noelle Kobayashi ◽  
Alberto Romagnolo ◽  
Brenton A. Wright ◽  
Carlo Alberto Artusi ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Phase I ◽  
Movement Disorders ◽  
Viral Vector ◽  
Gene Replacement ◽  
Therapeutic Benefit ◽  
Included Study ◽  
Acid Decarboxylase ◽  
Searching Strategy

Introduction: We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit.Methods: We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers).Results: We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers).Conclusion: Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.

scholarly journals Gene therapy for haemophilia: an update on progress in clinical trials

2015 ◽  
Vol 2 (1) ◽  
pp. 3-5
Author(s):  
Sarah Gilgunn
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Replacement Therapy ◽  
Viral Vector ◽  
Effective Means ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Spontaneous Bleeding ◽  
Factor Gene ◽  
Highly Effective

Abstract Clotting factor replacement therapy has proven a highly effective means of treating haemophilia A and B. But treatment involves frequent and lifelong infusion of factor concentrates and is generally prophylactic rather than curative. It is also extremely expensive, associated with inhibitor formation and does not fully abolish the potential for spontaneous bleeding. Gene therapy offers a potential cure for haemophilia, with the possible continuous expression of a clotting factor gene following the administration of a viral vector carrying the appropriate gene. Recent clinical trials of gene therapy for haemophilia have proven positive in selected patients and new studies are underway.

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