Gene Therapy in Clinical Applications: OVERVIEW: How Do We Translate Gene Therapy to Clinical Trials?

Messenger RNA (mRNA) is being extensively used in gene therapy and vaccination due to its safety over DNA, in the following ways: its lack of integration risk, cytoplasmic expression, and transient expression compatible with fine regulations. However, clinical applications of mRNA are limited by its fast degradation by nucleases, and the activation of detrimental immune responses. Advances in mRNA applications, with the recent approval of COVID-19 vaccines, were fueled by optimization of the mRNA sequence and the development of mRNA delivery systems. Although delivery systems and mRNA sequence optimization have been abundantly reviewed, understanding of the intracellular processing of mRNA is mandatory to improve its applications. We will focus on lipid nanoparticles (LNPs) as they are the most advanced nanocarriers for the delivery of mRNA. Here, we will review how mRNA therapeutic potency can be affected by its interactions with cellular proteins and intracellular distribution.

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The exosome journey: from biogenesis to uptake and intracellular signalling

Cell Communication and Signaling ◽

10.1186/s12964-021-00730-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sonam Gurung ◽

Dany Perocheau ◽

Loukia Touramanidou ◽

Julien Baruteau

Keyword(s):

Clinical Trials ◽

Plasma Membrane ◽

Scientific Community ◽

Cell Types ◽

Clinical Applications ◽

Clinical Development ◽

Intracellular Signalling ◽

Clinical Settings ◽

Health And Disease ◽

Adequate Definition

AbstractThe use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications.

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The United States’ Regulatory Environment Is Evolving to Accommodate a Coming Boom in Gene Therapy Research

Applied Biosafety ◽

10.1177/1535676019854866 ◽

2019 ◽

Vol 24 (3) ◽

pp. 147-152 ◽

Cited By ~ 2

Author(s):

Daniel Eisenman

Keyword(s):

United States ◽

Gene Therapy ◽

Clinical Trials ◽

The United States ◽

Regulatory Environment ◽

Evidence Based ◽

Regulatory Structure ◽

Regulatory Changes ◽

Current State ◽

Therapy Field

Introduction: A dramatic increase in the number of clinical trials involving gene-modified cell therapy and gene therapy is taking place. The field is on the verge of a boom, and the regulatory environment is evolving to accommodate the growth. Discussion: This commentary summarizes the current state of the field, including an overview of the growth. The United States (US) regulatory structure for gene therapy will be summarized, and the evolution of the oversight structure will be explained. Conclusion: The gene therapy field has recently produced its first FDA-approved therapeutics and has a pipeline of other investigational products in the final stages of clinical trials before they can be evaluated by the FDA as safe and effective therapeutics. As research continues to evolve, so must the oversight structure. Biosafety professionals and IBCs have always played key roles in contributing to the safe, evidence-based advancement of gene therapy research. With the recent regulatory changes and current surge in gene therapy research, the importance of those roles has increased dramatically.

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Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy

Neural Plasticity ◽

10.1155/2018/7108948 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Sara E. Ratican ◽

Andrew Osborne ◽

Keith R. Martin

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Optic Nerve ◽

Genome Editing ◽

Optic Neuropathy ◽

Single Gene ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Potential Use ◽

Hereditary Optic Neuropathy

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber’s congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber’s hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.

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Progress and prospects of gene therapy clinical trials for the muscular dystrophies

Human Molecular Genetics ◽

10.1093/hmg/ddv420 ◽

2015 ◽

Vol 25 (R1) ◽

pp. R9-R17 ◽

Cited By ~ 39

Author(s):

Niclas E. Bengtsson ◽

Jane T. Seto ◽

John K. Hall ◽

Jeffrey S. Chamberlain ◽

Guy L. Odom

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Muscular Dystrophies

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Convection-enhanced delivery to the central nervous system

Journal of Neurosurgery ◽

10.3171/2014.10.jns14229 ◽

2015 ◽

Vol 122 (3) ◽

pp. 697-706 ◽

Cited By ~ 85

Author(s):

Russell R. Lonser ◽

Malisa Sarntinoranont ◽

Paul F. Morrison ◽

Edward H. Oldfield

Keyword(s):

Drug Delivery ◽

Central Nervous System ◽

Clinical Trials ◽

Nervous System ◽

Convective Flow ◽

Clinical Applications ◽

Systemic Delivery ◽

Convection Enhanced Delivery ◽

The Central Nervous System ◽

Real Time Tracking

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

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Clinical Trials and Machine Learning: Regulatory Approach Review

Reviews on Recent Clinical Trials ◽

10.2174/1574887116666210715114203 ◽

2021 ◽

Vol 16 ◽

Author(s):

Diego Alejandro Dri ◽

Maurizio Massella ◽

Donatella Gramaglia ◽

Carlotta Marianecci ◽

Sandra Petraglia

Keyword(s):

Artificial Intelligence ◽

Machine Learning ◽

Clinical Trials ◽

Patient Safety ◽

Drug Discovery ◽

Clinical Applications ◽

Clinical Development ◽

Regulatory Approach ◽

National Competent Authorities ◽

Review Current

: Machine Learning, a fast-growing technology, is an application of Artificial Intelligence that has significantly contributed to drug discovery and clinical development. In the last few years, the number of clinical applications based on Machine Learning has constantly been growing. Moreover, it is now also impacting National Competent Authorities during the assessment of most recently submitted Clinical Trials that are designed, managed, or generating data deriving from the use of Machine Learning or Artificial Intelligence technologies. We review current information available on the regulatory approach to Clinical Trials and Machine Learning. We also provide inputs for further reasoning and potential indications, including six actionable proposals for regulators to proactively drive the upcoming evolution of Clinical Trials within a strong regulatory framework, focusing on patient safety, health protection, and fostering immediate access to effective treatments.

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EMEA and Gene Therapy Medicinal Products Development in the European Union

Journal of Biomedicine and Biotechnology ◽

10.1155/s1110724303209104 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 3-8 ◽

Cited By ~ 2

Author(s):

Marisa Papaluca Amati ◽

Francesco Pignatti ◽

Alexis Nolte ◽

Nirosha Amerasinghe ◽

Daniel Gustafsson ◽

...

Keyword(s):

Gene Therapy ◽

European Union ◽

Clinical Trials ◽

Good Clinical Practice ◽

Evaluation Agency ◽

The European Union ◽

Medicinal Products ◽

Regulatory Processes ◽

National Competent Authorities ◽

Practice Implementation

The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products.

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