Dornbusch thinks this strategy will spare patients serious side effects and “off-target” changes – unintended cuts elsewhere in the genome that could cause problems such as cancer.
The regions targeted by the company’s Crispr therapy are also found in a part of the genome that tends to stay the same even as HIV evolves. This is important because the virus mutates quickly and researchers don’t want a moving target.
This isn’t the first time scientists have tried to use gene editing in hopes of curing people living with HIV, but other efforts have focused on a protective mutation in a gene called CCR5. In the 1990s, scientists discovered that people with this natural mutation did not contract HIV when exposed to it. The mutation, known as delta 32, prevents the virus from getting inside immune cells. In 2009, California-based Sangamo Therapeutics used an older editing technology called zinc finger nucleases to add this protective mutation into patients’ T cells, an important part of the immune system. These tests had limited success.
In 2017, Chinese scientists combined Crispr with a bone marrow transplant in a trying to cure a patient with HIV and leukemia. In a typical transplant, stem cells from the donor are transferred to a recipient to replace their cancerous blood cells. These cells then form new healthy blood cells. To also treat the patient’s HIV, the researchers edited the donor stem cells with Crispr to deactivate CCR5. But after the transplant, only a small percentage of the patient’s bone marrow cells ended up with the desired change.
Then in 2018, Chinese scientist He Jiankui used Crispr to edit the CCR5 mutation in the genomes of twin babies to make them resistant to HIV. In charge of ethical breachesthe experience has been widely condemned by scientists. His research was suspended by the Chinese government and he served a three-year prison term. While the twins were born healthy, only some of their cells were successfully altered, meaning the girls may not actually be immune to HIV.
From 2022, two people have now been cured of HIV after receiving bone marrow transplants from donors CCR5. Known as the patient of Berlin and the london patient, both had cancer and received transplants to treat their disease. But these transplants are not a viable option for most people – they are very risky and donors with the delta 32 mutation are rare. But a third person was declared cured of HIV earlier this year after receiving a new type of transplant involving umbilical cord blood.
The circumcision trial will ultimately enroll nine participants and test three doses to see which is most effective. Investigators will measure each person’s viral load and CD4 count before receiving treatment and after they stop taking antiretroviral drugs. The ultimate goal is to reduce the viral load to an undetectable level, ie less than 200 copies of HIV per milliliter of blood. At this level, HIV cannot be sexually transmitted.
The challenge for Excision will be to get Crispr to enough cells to bring HIV down to undetectable levels. The company uses a modified virus to deliver the gene-editing components to patients’ HIV-infected CD4 cells. But so far there is little human data on the effectiveness of Crispr when administered directly to the body. “It’s possible you catch the virus at such low levels that if a person’s immune system was intact, they might be able to keep the virus at bay so they don’t have to take treatment anymore. antiretroviral,” says Rowena Johnston, Vice President. President and Director of Research of amfAR, the Foundation for AIDS Research.
And even though these drugs are very effective, says Johnston, many people would prefer to be completely free of the virus. A single infusion of Crispr, if it works, would eliminate the need for daily pills. “People living with HIV still live with a lot of stigma and internalized shame,” she says. “I think a cure is something that responds much better to that than lifelong therapy, however easy that therapy becomes.”