Doing CRISPR gene editing while fetuses are in the womb could make it easier to treat inherited conditions, especially those affecting tissues such as the heart or muscles.
Kiran Musunuru at the University of Pennsylvania and his colleagues have tested gene editing in monkeys, and found that it was far more effective when given before birth. 鈥淲hat we found was astounding,鈥� he says. 鈥淚t opens up the opportunity to treat diseases that have been very hard to treat after birth.鈥�
Musunuru wants to tackle inherited metabolic disorders that mean, say, the liver is unable to break down certain toxins. These conditions can cause irreversible damage to organs like the brain the longer they go untreated, and for many there are no effective treatments. In these cases, it would be best to do gene editing before birth, he says. There is precedent for fetal interventions: some physical problems are now corrected by surgery on fetuses as early as 16 weeks into pregnancy because the outcomes are better.
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鈥淚鈥檓 talking about those unusual cases where there鈥檚 a devastating genetic condition that鈥檚 not diagnosed until the pregnancy is already well established,鈥� says Musunuru. 鈥淎re we going to really wait until birth to treat? If you insist on that, then some of these patients are going to suffer irreversible harm before they鈥檙e born, and they鈥檙e going to be much worse off than if you were to treat before birth.鈥�
To pave the way for prenatal gene editing, Musunuru and his team are doing tests in animals including monkeys. Their approach involves packaging mRNAs coding for gene-editing machinery into fatty parcels called lipid nanoparticles and injecting them into the umbilical cord.
In adults, almost all of these nanoparticles are taken up by liver cells, meaning almost all the editing happens in those cells. For now, the only way to target tissues such as muscle is to use viruses to deliver the gene-editing machinery, but this is problematic, not least because viruses can trigger an immune response. 鈥淭he general consensus is they just don鈥檛 work that well,鈥� says Musunuru.
He and his team have yet to publish their research, but he told 快猫短视频 that when they injected lipid nanoparticles into monkey fetuses, there was even more editing in the liver than in adults for an equivalent dose. To their surprise, there was also extensive editing in the heart and the diaphragm muscle, and to a lesser extent in other muscles and the kidney.
This means the approach could be used to treat heart conditions 鈥� and by optimising the lipid nanoparticles, Musunuru thinks it will be possible to get even more extensive editing in muscles and treat skeletal muscle conditions, too. It is likely that in fetuses the barriers between tissues aren鈥檛 yet fully established, he says, meaning the lipid nanoparticles can reach places they normally can鈥檛.
Fetuses are also growing rapidly, says Robin Lovell-Badge at the Francis Crick Institute in London, who isn鈥檛 involved in the work, and gene editing works better in rapidly dividing cells.
Lovell-Badge says other groups are also working on developing prenatal gene-editing treatments. If this is done before the immune system develops, it could also avoid any immune responses to viruses used for delivery and other components of the treatment.
鈥淗owever, prenatal genome editing does mean that there are two patients 鈥� the fetus and the mother. This makes it more complex in several respects,鈥� he says.
Another issue is that genetic disorders need to be identified early in pregnancy for prenatal gene editing. At present, genetic screening is done after birth, and only in a few countries and for a few conditions. But Musunuru says no one is screening fetuses for such disorders because nothing can be done if one is identified, and that this will change if there are treatment options. 鈥淚t鈥檚 a chicken and egg problem,鈥� he says.
