The plan to ease restrictions on genetic modification in New Zealand promises advances everywhere from food production to human health. To read Part I of the Listener’s Releasing the Genie feature, go here. In Part II, science writer Andrea Graves looks at how gene editing could help to combat diseases with a genetic components, from cancer to autoimmune conditions.
Andrew Shelling heads the Centre for Cancer Research at the University of Auckland, and he’s excited by what’s unfolding. “Every week, I read the medical journals like the New England Journal of Medicine or The Lancet, and there’s a new study or trial showing this technique leads to good outcomes,” he says.
At the forefront are blood cancer treatments, particularly forms of leukaemia and lymphoma. “There are CAR-T recipients walking around New Zealand,” says Shelling. T cells are powerful immune cells, and 30 people had theirs enhanced to treat their lymphoma in a safety trial at Wellington’s Malaghan Institute of Medical Research. Their blood was drawn to obtain their T cells, which were then modified to add a gene that produces a chimeric antigen receptor, or CAR. The CAR helps the T cells recognise the cancer cells as foreign, so when CAR-T cells are returned to the patient, they attack the cancer cells. They cause remission in about half of all cases, and this type of treatment is now standard in some overseas countries. A larger trial has just been approved here.
It’s the ability to target the mutations in each person’s cancer cells that makes genetic treatments so exciting. It’s about treating the mutation, not which part of the body it’s in.”
Shelling used to test for mutations in BRCA (breast cancer) genes in his laboratory. These genes make proteins that help repair damaged DNA, but some people inherit certain BRCA mutations that thwart that protective function. They experience higher rates of not only breast cancer, but also ovarian and prostate cancer. He says such single-gene mutations are prime targets for CRISPR-guided treatments. These treatments are still in development, partly because it’s harder to access cells in solid tumours than in blood.
“How can you target all of the breast, ovary and prostate and correct every cell? There may be ways, such as injecting into the blood supply that feeds the tissue.”
In some cases the treatment is likely to be transformative. That appears to be the case for people with hereditary angioedema. The first human trial began nearly three years ago in Auckland with patients receiving a single infusion of a CRISPR-based treatment that deactivates the problematic gene. It almost eliminated the severe, painful swelling attacks that characterise the disease and is expected to be a permanent cure for the symptoms.
CRISPR could heal other diseases that result from defective genes, either by delivering an effective gene or knocking out a mutant gene. “There are about 7500 diseases where we know there’s a direct link with the problem gene or genes,” says Shelling. “For some very serious genetic diseases, this might be the best solution.” They include Huntington’s disease, cystic fibrosis, Duchenne muscular dystrophy and more, and they’re the focus of intensive research, most of it still limited to labs. For a very few – specifically the inherited blood conditions sickle cell disease and beta thalassemia – there are gene treatments already approved by the US Food and Drug Administration.
Even in conditions where the genetic component is not strong, such as diabetes, Alzheimer’s and cardiovascular disease, lab studies are showing potential for gene editing to create more healthy cells, says Shelling. There’s hope for diseases caused indirectly by genes, too, with the first human trial just completed infusing people with a gene-editing agent that tackles familial high cholesterol.
Infectious disease is also in the firing line, with clinical trials starting on treatments that use gene editing to silence or remove the viruses that cause hepatitis B and HIV.
Gene editing is also being used to disarm bacteria that cause antibiotic-resistant urinary tract infections.
Another focus is autoimmune diseases – for example, type 1 diabetes, which is caused by the immune system destroying pancreas cells that produce insulin. Implanting healthy donor pancreatic cells fails unless patients take immunosuppressive drugs, but a new approach being trialled implants gene-edited cells that produce insulin but evade the immune system. Some chronic autoimmune conditions that cause organ damage, such as lupus, may also be treated with gene technologies: in one small trial, CAR-T therapy successfully targeted the problematic immune cells and led to remission for lupus patients.
Shelling says most institutions in New Zealand already work on genetic treatments for disease, and he’s looking forward to eased legislation.
One thing that’s not in the pipeline, however, is editing an embryo’s genes. The treatments being developed often alter a person’s own genes, but the change won’t be passed to their children. Such inheritance can only happen if genes are altered in embryos, which was done with three children born in 2018 and 2019. The scientist responsible claimed it would make them immune to HIV (one of each set of parents had HIV), and raised the spectre of “designer babies” with their genetic makeup enhanced for traits such as athletic ability. The scientist was imprisoned in China for violating medical regulations and widely condemned by other scientists.
“With time, I guess it will happen,” says Shelling. “But at present, there are too many off-target effects. There’s an effective moratorium on it. That shows how seriously we take these things.”
