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Miguel Forte, MD, PhD
ISCT President
mC4Tx
Belgium

Cell and gene therapy has come a long way, particularly since 2017 when the fantastic clinical outcomes and patient value that had been reported over the previous 5 year promised a great commercial opportunity with regulatory approvals. Gene therapy, first ex-vivo and more now in-vivo, is raising real hopes of long-term benefit, cure and potential gene correction and somehow worrying amplification.

Nevertheless, the adoption of these therapies has been very limited, well below current patient need, and also surely commercial expectations from developers and investors. Reasons for that slow uptake and limited use are multiple. The cost, capacity to manufacture, ability, knowledge, and structure to administer these therapies are certainly determinant for that low below expectations use but other aspects namely the perception of these therapies from the final users are also relevant. For all these reasons, one would suggest that despite the fantastic efficacy with these approaches and the curative value they represent, these products still require adequate launches to underscore the value proposition and educate users.

Gene therapy including Human genome editing has great potential to improve human health and medicine. Currently, gene editing technologies are used on somatic cells, which is non-heritable. These approaches are represented by the several CAR-T approved products on the market and multiple others in development for oncology indications now also expanding to other indications like autoimmunity. The clinical results and consequent value to patients with these therapies have already been very impactful in the way we practice medicine with recognized benefit for patients. The gene engineering with these therapies involves the transfer of genetic material into the cell with subsequent integration in the cell genome. This integration raises the potential concern of insertional mutagenesis but despite the identification of post-therapy malignancies, the causality has not been established (1 and 2). This is, correctly, a point focus on regulatory discussions of new products and continued surveillance in post-approval use leading to very relevant real-world-evidence of the benefit/risk ratio of these products. Nevertheless, the potential risks involved remain contained in the patient, in this somatic approach, and any benefit/risk considerations revolve around the individual patient benefit and potential risk. Societal implications result from the evolution of medical practice and the opportunity to give new hopes to manage significant, debilitating and lethal diseases.

In addition to somatic gene editing, which is non-heritable, there are other gene editing approaches that could involve in vitro studies on early embryos, gametes or their precursors, also non-heritable, and heritable approaches, where embryos subject to genome editing are used to establish pregnancies and potentially create individuals who could pass on the gene edit to their offspring. These are referred as germline editing, in contrast to somatic editing. The key difference is the containment of the benefit/risk discussion to the individual targeted with the therapeutic approach versus the implications of heritable, population expandable, procedures. 

Several organizations and interested parties, recognizing the risks, our limited knowledge and the potential technical and ethical implications together with risk for deviation associated with germline editing, have worked in discussing and trying to analyze, advise and regulate practices in this field. Namely, the World Health Organization (WHO) established a global, multidisciplinary expert advisory committee (the Expert Advisory Committee on Developing Global Standards for governance and Oversight of Human Genome Editing) to examine the scientific, ethical, social and legal challenges associated with human genome editing. This committee has issued an extensive, albeit preliminary, report published in 2021 (3).

In fact the risk of research misconduct is real and at least one example is known. In November 2018, the media reported on a Chinese scientist who had created the world’s first gene-edited babies using CRISPR technology. He said his goal was to provide children with resistance to HIV, the virus that causes AIDS. When his experiment became public knowledge, twin girls had already been born and a third child was born the following year. The fate of these three children, and whether they have experienced any negative long-term consequences from the embryonic genome editing, remains a closely guarded secret. This researcher, He Jiankui, who performed the first known human embryo edits resulting in live births, was prosecuted and convicted in China, but interestingly, the prosecution was based on practicing medicine without a license and not specifically based on a provision governing assisted reproduction or genome editing. At the time, ISCT issued a press release (reference) condemning the research and expressing concern on the risks associated. Subsequently  in 2019, an international group of ethicists and researchers called for a moratorium on the clinical use of heritable human genome editing, which was supported by the US National Institutes of Health. The organizing committee of the third international summit on human genome editing said in 2023 that heritable human genome editing “remains unacceptable at this time” (5).

A recent event, that took place in May this year but only became noticed recently, has raised this topic to the top of the discussions as researchers voiced concerns with the fact that South Africa updated its health-research ethics guidelines to include a new section on heritable (or germline) human genome editing. It was suggested that this could put them one step closer to accepting the controversial technique — which involves introducing genetic changes to sperm, eggs or embryos, such that the modifications will be passed down through successive generations (5 6). It should be stressed that the update of the ethics guidelines does not equate to legal recognition of germline gene editing. Several entities have expressed that it remains illegal to perform such clinical research. It is also very important to have alignment between different countries and geographies on the position to germline heritable clinical research to prevent the temptation of people and patient movements seeking these approaches in areas or countries with different, potentially more permissive, supervision, authorizations and control.

In a recent publication (reference), that is also included in the WHO report, has looked at the existing legislation in a total of 96 countries and concluded that no country legally authorizes the conduct of heritable human genome editing (for reproduction). It also documented that research is expressly prohibited in 70 countries, prohibited with exceptions in 5 countries and 21 are indeterminate or do not have relevant information. One particular note, also stressed in the paper, are multiple country positions on moratorium or prohibition of germline heritable clinical research like the Oviedo Convention from the Council of Europe and ratified by 29 countries (reference).

Given the implications and high profile of discussions and actions, ethical, legal and technical, it is of the upmost importance that implicated international organizations involved in leading gene therapy, take position and work in collaboration to discuss and elaborate guidance aiming at a governance framework that intends to provide those responsible for the oversight of genome editing, those doing research and the society at large with the tools and guidance needed, putting forward values and principles to inform both how and what decisions are made. With this intention ISCT, and its Ethics Committee (ISCT Ethics of Cell & Gene Therapy Committee) is planning to collaborate with other organizations namely ARM and ASGCT to address these topics of gene therapy including germline heritable gene editing! The value and potential of gene therapy is enormous with expectation of very significant value for patients, the practice of medicine and all stakeholders, yet, it needs to be done consciously, ethically, with good science and clear risk aware governance.

References 

1. G. Kobbe, et all, Aggressive Lymphoma after CD19 CAR T-Cell Therapy (2024) N Engl L Med 391;13
2. Willyard, C. Cancers from CAR-T-Cell Therapies: What the data say. (2024) Nature; Vol 629; 22-24
3. HUMAN GENOME E DITING: A FRAMEWORK FOR GOVERNANCE. WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. (2021) WHO
4. Wild, S. Will South Africa become first country to accept controversial form of human genome editing? Scientists raise the alarm following updated research ethics guidelines on heritable human genome editing. (2024) Nature News, https://doi.org/10.1038/d41586-024-03643-4
5. Baylis, F. South Africa amended its research guidelines to allow for heritable human genome editing. (2024) https://theconversation.com/south-africa-amended-its-research-guidelines-to-allow-for-heritable-human-genome-editing-241136#:~:text=A%20little%2Dnoticed%20change%20to,to%20create%20genetically%20modified%20children.
6. Baylis, F. Human Germline and Heritable Genome Editing: The Global Policy Landscape (2020) The CRISPR Journal, Volume 3, Number 5

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