The Future of Cell and Gene Therapy: Experts’ Perspectives

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Chapter summaries

Five biggest trends of AAV-based gene therapies

Adeno-associated virus (AAV) was first discovered in the mid-1960s, then cloned for the first time in the early-1980s. However, it wasn’t until 1995 that the first human patients were treated with AAV for cystic fibrosis. The first meaningful clinical efficacy followed in 2008 in the retinal diseases space – a journey that culminated in 2017 with the regulatory approval of Spark Therapeutics’ Luxturna. In the intervening years, Glybera – an AAV-based gene therapy for the ultra-rare disease, hereditary lipoprotein lipase deficiency (LPLD) – gained market approval in Europe. However, it was subsequently withdrawn from the market due to its high cost. Most recently, in 2019, Zolgensma became the second AAV gene therapy to be approved by the US FDA, for spinal muscular atrophy (SMA). This potted history demonstrates that AAV has been on a long journey from initial discovery to successful clinical application. However, AAV-based gene therapy now stands on the cusp of bringing its’ significant, often curative benefits not just to dozens of patients, but potentially thousands. Here, we explore five key trends and issues in the field today, which reveal a pathway to further product approvals and more widespread adoption by healthcare systems worldwide.

Regulatory expectations & guidelines around AAV gene therapy

The first US Food and Drug Administration (FDA) regulatory guidance specifically for the cell and gene therapy field emerged in the 1990’s, addressing preclinical R&D and manufacturing, and to a lesser extent, clinical aspects. Since then, the regulatory framework surrounding adeno-associated virus (AAV)-based gene therapies has been modernized considerably, particularly in the last 5 years. Here, we highlight some key aspects of evolving regulatory thinking and guidance around the space that have major repercussions for AAV-based gene therapy developers.

Five biggest trends of gene-modified cell therapy

The gene-modified cell therapy field continues to grow apace, particularly in the oncology arena, which dominates both preclinical and clinical applications. For example, recent data from The Cancer Research Institute suggests there are 2,756 cell therapies in development for cancer indications in 2022, up from 2,031 in 2021. Furthermore, this growth is reflected in the number of studies at every stage of development, from preclinical studies to pivotal clinical trials, and across every major immune cell type/modality, including chimeric antigen receptor T cell (CAR-T) cells, natural killer (NK) cells, T cell receptor T cells (TCR-Ts), and tumor-infiltrating lymphocytes (TILs). The American Society for Gene and Cell Therapy (ASGCT) concurs, stating in its Gene, Cell, & RNA Therapy Landscape Q2 2022 QuarterlyData Report that in the year from Q1 2021, the overall gene therapy pipeline of products in preclinical to pre-registration studies increased by 16%. (Ex vivo genetically modified cell products comprised 73% of this total pipeline – a record high share).

Harnessing analytical technologies to modify your AAV development workflow

In ‘Five biggest trends of AAV-based gene therapies’, we highlighted some key challenges relating to the development and manufacture of AAV-based gene therapies, many of which require developers to alter their workflows. Here, we delve deeper into these challenges and look at how gene therapy developers can make the changes required to address them. In particular, we explore the hurdles in measuring and reducing immunogenicity in the clinic, in better understanding potency by leveraging multiple analytical techniques, and in cultivating a robust understanding of critical quality attributes to ensure safety and efficacy.

Tips for meeting regulatory guidelines for AAV development

Regulatory guidance for AAV-based gene therapy has evolved rapidly over the past 5 years in particular. Here, we delve deeper into the resultant pain points for developers and manufacturers, offering advice on how best to alleviate or avoid them in order to streamline regulatory compliance.

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: None

Disclosure and potential conflicts of interest: Lorenz C discloses he is a full time employee of Astellas Gene Therapies. Naik S discloses she is part of BIO regenerative medicine committee and has been elected as co-chair (unpaid). The authors have no other conflicts of interest to disclose. Sourdive D discloses he has royalties/licenses from Allogene Therapeutics. He also has financial/non-financial interests at University of Texas MD Anderson Cancer Center. 

Funding declaration: White M received financial support for the research, authorship and/or publication of this article from Bio-Rad Inc. Sasu B received financial support for the research, authorship and/or publication of this article from Allogene Therapeutics.

Article & copyright information

Copyright: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2022 Bio-Rad Inc. Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: This is eBook was written by David McCall, Editor, Cell and Gene Therapy Insights, with insights and contributions from Chris Lorenz, Santoshkumar Khatwani, Mark White, Snehal Naik, David Sourdive, Michael Leek, Barbra Sasu and Adrian Bot.

Publication date: Oct 13 2022.