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Germline gene therapy (GGT): its potential and problems

A Scientia News Biology and Genetics collaboration

Introduction


Genetic diseases arise when there are alterations or mutations to genes or genomes. In most acquired cases, mutations occur in somatic cells. However, when these mutations happen in germline cells (i.e. sperm and egg cells), they are incorporated into the genome of every cell. In other words, should this mutation be deleterious, all cells will have this issue. Furthermore, this mutation becomes inheritable. This is partly why most genetic diseases are complicated to treat and cure.


Gene therapy is a concept that has been circulating among geneticists for some time. Indeed, addressing a disease directly from the genes that caused or promoted it has been an attractive and appealing avenue of therapies. The first successful attempt at gene therapy dates back to 1990, using retrovirus-derived vectors to transduce the T-lymphocytes of a 4-year-old girl with X-linked severe combined immunodeficiency disease (SCID-X1) with enzyme adenosine deaminase (ADA) deficiency. The trial was a great success, eliminating the girl's disease and marking a great milestone in the history of genetics.


Furthermore, the success of viral vectors also opened new avenues to gene editing, such as zinc finger nucleases and the very prominent CRISPR-Cas9. For example, in mid-November 2023, the UK Medicines and Healthcare products Regulatory Agency or MHRA approved the CRISPR-based gene therapy, Casgevy, for sickle cell disease and β-thalassemia. It is clear that the advent of gene therapies significantly shaped the treatment landscape and our approach to genetic disorders. However, for most of gene therapy history, it is done almost exclusively on somatic cells or some stem cells, not germline cells.


How it works


As mentioned, inherited genetic disease-associated mutations are also present in germline cells or gametes. The current approach to gene therapy targets genes of some or very specific somatic or multipotent stem cells. For example, in the 1990 trial, the ADA-deficient SCID-X1 T-lymphocytes were targeted, and in recently approved Casgevy, the BCL11A erythroid-specific enhancer in hematopoietic stem cells. The methods involved in gene therapies also vary, each with advantages and limitations and carrying some therapeutic risks.


Nevertheless, when aiming to treat genetic diseases, gene therapy should answer two things: how to do it and where.


There are a few elucidated strategies of gene therapies. Unlike some popular beliefs, gene therapies do not always directly change or edit mutated genes. Instead, some gene therapies target enhancers or regulatory regions that control the expression of mutated genes. In other cases, such as in Casgevy, enhancers of a different subtype are targeted. By targeting or reducing BCL11A expression, Casgevy aims to induce the production of foetal haemoglobin (HbF) (Frangoul et al., 2021), which contains the γ-globin chain as opposed to the defective β-chain in the adult haemoglobin (HbA) of sickle cell disease or β-thalassemia. 


Some gene therapies can also be done ex vivo or in vivo. Ex vivo strategies involve extracting cells from the body and modifying them in the lab, whilst in vivo strategies directly modify the cell without extraction (e.g. using viral/ non-viral vectors to insert genes). In essence, the list of strategies for gene therapies is growing, each with limitations and a promising prospect of tackling genetic diseases.


These methods aim to “cure” genetic diseases in patients. However, the strategies mentioned above have all been researched using and, perhaps, made therapeutically for somatic or multipotent stem cells. Germline gene therapy (GGT), involves directly editing the genetic materials of germline cells or the egg and sperm cells before fertilisation. This means if it is done successfully, fertilisation of these cells will eliminate the disease phenotype from all cells of the offspring instead of only effector cells. Potentially, GGT may eradicate a genetic disease for all future generations. Therefore, it is an appealing alternative to human embryo editing, as it achieves similar or the same result without the need to modify an embryo. However, due to its nature, its advantage may also be its limitation.


Ethical issues


GGT has the potential to cure genetic disorders within families. However, because it involves editing either the egg or sperm cells before fertilisation, there are prominent ethical issues associated with this method, like the use of embryos for research and many more.


Firstly, GGT gives no room for error. Mistakes during the gene modification process could cause systemic side effects or a harsher disease than the one initially targeted, leading to a multigenerational effect. For example, if parents went to a clinic to check if one/both their germ cells have a gene coding for proteins implicated in cystic fibrosis, an off-target mistake during GGT may lead to their child developing Prader-Willi Syndrome or other hereditary disorders caused by editing out significant genes for development.


Secondly, an ecological perspective asserts that the current human gene pool, an outcome of many generations of natural selection, could be weakened by germline gene editing. Also, there is the religious perspective, where editing embryos goes against the natural order of how god created living creatures as they should be, where their natural phenotypes are “assigned” for when they are alive. 


Another reason GGT may be unethical is it leads to eugenics or creating “designer babies”. These are controversial ideas dating back to the late 19th century, where certain traits are “better” than others. This implies they should appear in human populations while individuals without them should be sterilised/killed off. For instance, it is inconceivable to forget the Nazi Aktion T4 program, which sought to murder disabled people because they were seen as “less suitable” for society.


Legal and social issues


Eugenics is notorious today because of its history. Genetic counselling may be seen like this as one possible outcome may be parents who end pregnancies if their child inherits a genetic disease. Moreover, understanding GGT’s societal influences is crucial, so clinical trial designs must consider privacy, self-ownership, informed consent and social justice. 


In China, the public’s emotional response to GGT in 2018 was mainly neutral, as shown in Figure 1, but some of the common “hot words” when discussed were ‘mankind’, ‘ethics’, and ‘law’. With this said, regulations are required with other nations for a wider social consensus on GGT research.


In other countries, there are stricter rules for GGT. it is harder to conduct experiments using purposely formed/altered human embryos with inheritable mutations in the United States because the legal outcomes can include prison time and $100,000 fines. Furthermore, when donors are required, they must be fairly compensated, and discussing methodologies is crucial because there are issues on how they can impact men and women.


South Africa has two opposing thoughts on GGT or gene editing. Bioconservatism has worries about genetic modification and asserts its restrictions, while bioliberalism is receptive to this technology because of the possible benefits. Likewise, revisions to the current regulations are suggested, such as rethinking GGT research or a benefit-risk analysis for the forthcoming human.


Conclusion


Overall, gene therapies have transformed the therapeutic landscape for genetic diseases. GGT is nevertheless a unique approach that promises to completely cure a genetic disease for families without the need to edit human embryos. However, GGT’s prospects may do more harm than good because its therapeutic effects are translated systemically and multigenerationally. On top of that, controversial ideas such as designer babies can arise if GGT is pushed too far. Additionally, certain countries have varying regulations due to cultural attitudes towards particular scientific innovations and the beginning of life. Reflecting on the ethical, legal and social issues, GGT is still contentious and probably would not be a prominent treatment option anytime soon for genetic diseases.



Written by Sam Jarada and Stephanus Steven


Introduction, and How it works by Stephanus

Ethical issues, and Legal and social issues by Sam

Conclusion by Sam and Stephanus



References:

Cavazzana-Calvo, M. et al. (2000) ‘Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease’, Science, 288(5466), pp. 669–672. doi:10.1126/science.288.5466.669.


Demarest, T.G. and Biferi, M.G. (2022) ‘Translation of gene therapy strategies for amyotrophic lateral sclerosis’, Trends in Molecular Medicine, 28(9), pp. 795–796. doi:10.1016/j.molmed.2022.07.001. 


Frangoul, H. et al. (2021) ‘CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia’, New England Journal of Medicine, 384(3), pp. 252–260. doi:10.1056/nejmoa2031054.


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