New book chapter on law/bioethics of somatic cell genome editing (and sickle-cell diseases)

After a long journey that should have been no surprise whatsoever (not when one looks at the scale and size of this volume), a book chapter I authored with Emeritus Distinguished Prof Dianne Nicol from the University of Tasmania’s Centre for Law and Genetics, way back in 2021, has now been published.

The chapter deals with the bioethics of somatic cell genome editing, which, so it is said — and as the literature mostly suggests — does not raise many ethical issues at all. But that, of course, is not quite right. ‘SCGE’ — like all cellular therapies — presents an array of bioethical and biopolitical challenges to patients, including those related to safety and accessibility.

This is not least because those treatments that are now emerging, the frontrunner among which is exa-cel (previously CTX-001), are designed to treat hemoglobinopathies — that is, blood diseases — that disproportionately impact people in sub-Saharan Africa. And it appears they will be prohibitively expensive.

Additionally, the treatment of these disorders may have impacts beyond our current predictions. After all, the sickle-shaped red blood cells (RBCs) that this treatment will treat and resolve have also been identified as providing protection against malaria. That’s because haem — a component of haemoglobin — was found to confer advantage in experimental studies.

In essence, haem, which is present in a free form in the RBCs of mice with the sickle cell trait, but mostly absent from mice without the trait, seems to protect against malaria. When mice without sickle cells were injected with haem, and then later infected with malaria, it was found that the injected haem helped to guard against malaria in those previously normal — and malaria-unprotected — mice. It follows, as the authors note, that ‘Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection.’ The question, then, is whether this conferred advantage will change at all among those who are treated for sickle-cell diseases, such as beta thalassemia, with exa-cel. I should note, however, this is not a question explicitly addressed in the chapter.

Instead, our chapter deals with the technical history of somatic cell genome editing, and the way in which this form of genome editing is different to heritable genome editing. SCGE is not heritable because it is performed on post-natal humans whose gametes (reproductive cells) have fully materialised and developed. Once the gametes have developed, they maintain their genomic content for life (as far as we know). By contrast, genome editing prior to fertilisation (ie, genome editing performed on IVF or ART embryonic cells prior to their being fertilised) is heritable, and will carry over to the future generations.

Although the science of SCGE might sound relatively boring when compared to heritable human genome editing, it really is not. For a start, SCGE is happening right now. It could be decades — perhaps centuries — before we start editing pre-fertilised human embryos using CRISPR Cas-9. But we are using the same technology — CRISPR Cas-9 endonucleases — on adult stem cells today. Speaking generally of SCGE (and not specifically about exa-cel), the process is essentially this:

  • cells are removed from the adult patient’s body;
  • the patient undergoes ablative therapy to kill all pathogenic/diseased cells (eg, the sickle RBCs) in their body (and clearly they are in a very serious condition at this time);
  • the patient’s removed cells are shipped off to a laboratory, where they are subjected to the action of the endonuclease (the CRISPR) through flow electroporation or a similar technique (which enables the CRISPR to work by manipulating the materials at a nuclear level);
  • the resulting ‘product’ of the ‘manufacturing’ process is the therapeutic good (ie, exa-cel)
  • the CRISPR-Cas is essentially a cutting and repair tool that cuts and then repairs double-strand breaks in human DNA (changing the nucleotides as it repairs them);
  • the repairs created by the CRISPR-Cas are ‘guided’ or played out on a ‘template’; and
  • the edited cells, which are not affected by disease (because they have been edited) are then reinfused into the body, and replace the cells that existed previously

There is much more to say about SCGE, but that is all in the chapter. I also wrote about it earlier this year, on this website, here.

But it’s great to have the book chapter finally out there. I attach a few images of the contents pages to illustrate the huge scope of the volume — which is one of two. The book’s full title is the Handbook of Bioethical Decisions, Volume I: Decisions at the Bench. It is edited by Erick Valdés and Juan Alberto Lecaros, whom I thank for including our chapter; and it is published by Springer.

Updates from ‘Cellular Horizons’

Medical Research Future Fund project investigating how to to improve decisions about accessing cellular therapies

I recently presented updates from our MRFF project, which investigates how to improve decision-making, primarily among patients, about how and whether to access cellular therapies. The project has so far focused primarily on mesenchymal stem cell interventions: ie, ‘regenerative medicine’ treatments for osteoarthritis and conditions involving cell dysfunction. As a chief investigator in the ‘legal and regulatory affairs’ sub-team on the project, my focus has been on how these treatments are regulated.

New cellular therapies

However, as new cell-based interventions emerge as we speak, the project will likely also consider these novel interventions. In a very recent trial, immune cells (CAR-T cells) have been ‘programmed’ to attack cancerous T-cells by means of CRISPR ‘base editing.’ Specifically, this trial is aimed at treating a patient with T-cell acute lymphoblastic leukemia, or T-ALL.

There have been two issues for treating this disorder in the past.

The first relates to what is called T-cell aplasia. This is a process whereby the antigens on the T-cells are attacked, which destroys not only the cancerous T-cells but also destroys the normal T-cells. The means that T-cell numbers are decreased significantly.

Cell aplasia happens when patients undergo CAR T-cell therapy. Thus, when the cancer is a B-cell malignancy, the patient will generally experience B-cell aplasia. However, with B-cell aplasia, immunoglobulin replacement therapy can be administered to manage the problem. This is not so for T-cell aplasia. T-cell aplasia is not generally tolerated in humans, and persistent T-cell aplasia is life threatenting. Therefore, CAR T-cell therapy has generally not been possible for T-ALL.

The second issue is that CAR-T cells programmed to recognise and destroy T-cell antigens will inevitably attack healthy T-cells too in what is described as ‘T-cell fratricide.’ Sometimes, this problem is called ‘T v T’ fratiricide. This is described in the video below, which is a basic introduction to base editing published by Great Ormond Street Hospital:

While it is an extremely complicated molecular process, in CRISPR base editing, nucleotide bases in donor cells are edited at the atomic level so that the gene for CD7 (a genetic marker in blood cancers) is changed from cytosine to a thymine. In this process, the base editing produces a so-called ‘stop codon’ that terminates the production of CD7 (acting like a molecular ‘full-stop’). These edited cells are then transplanted into the patient to treat relapsed lymphoblastic leukaemia.

In an article published in Leukemia, authored by the team that are conducting the trial, the authors write that

Base editing offers the possibility of seamless disruption of gene expression of problematic antigens through creation of stop codons or elimination of splice sites. We describe the generation of fratricide-resistant T cells by orderly removal of TCR/CD3 and CD7 ahead of lentiviral-mediated expression of CARs specific for CD3 or CD7. Molecular interrogation of base-edited cells confirmed elimination of chromosomal translocations detected in conventional Cas9 treated cells.

While it is far too early to determine whether base editing might present an option to patients with T-ALL and whose options are exhausted, it is promising to see that base editing appears to be possible in humans. Using CRISPR base-edited cells in humans represents a new form of cellullar therapy — it could be called somatic cell genome editing; the only other trial for SCGE that I’m aware of is the trial for exagamglogene autotemcel  or exa-cel (formerly known as CTX-001); however, that is not a base-edited genome therapy. Rather, Exa-cel uses CRISPR to treat blood disorders (hemoglobinopathies) such as sickle-cell disorder.

Unlike T-ALL base editing treatment above, where base editing is applied to donor cells, exa-cel edits the patient’s own cells (ie, it is an autologous treatment), which are removed prior to the treatment. With the cells removed, the patient is given ablative therapy while the hematopoietic stem cells are edited using CRISPR-Cas9 to produce high level of fetal hemoglobin. This treatment promises to ensure that vaso-occlusive crises (blocked blood flow, depriving tissues of oxygen, and usually caused by the ‘sickle’ shape of the red blood cell), which is a symptom of the blood disorders, is avoided.

New Priority Review Pathway for Biologicals

In the context of such cellular therapies emerging in recent times, the Australian drug regulator, the Therapeutic Goods Administration, has recently introduced new expedited pathways for drug sponsors and manufacturers to fast-track novel biological therapies (another name for therapies involving cell and tissue products) through the approval process. In a recent article published in the Journal of Law and Medicine, our team analysed the new ‘priority pathway,’ which has since been approved. We also wrote a submission to the TGA, which can be found here.

In early December, I presented some of our work on these matters to another team of experts working on cellular therapies in Australia. Presentation slides from that meeting are available here.

Earlier in the year, in April, I presented a brief introduction on the same subject to our internal team. That presentation is also made available here.