HIV continues to represent a global health burden, with the World Health Organization (WHO) estimating that, in 2022, there were 39 million people living with the virus. But there is still no effective cure for it. The only option patients have is antiretroviral therapy, which, although it represents a major milestone in HIV treatment and has saved countless lives, it needs to be taken everyday in order to suppress viral replication.
On top of that, antiretrovirals can be toxic to the body, potentially causing a broad range of both short-term and long-term adverse effects. For example, patients taking them often struggle with cardiovascular disease and brain dysfunction.
So, despite the fact that antiretroviral drugs have turned HIV infections from an instant death sentence into a chronic, treatable disease, the ultimate goal is to find a cure for this challenging virus.
And CRISPR gene editing technology may well hold the answer.
It has been found that some people are naturally immune to HIV. This is thanks to a genetic mutation on the gene that encodes CCR5, which is the protein on the surface of immune cells that the virus uses to enter and infect them. But people with this mutation are missing part of the CCR5 protein, meaning the virus cannot bind to it.
This means that, in theory, CRISPR can be used to edit CCR5 in order to introduce this mutation to eradicate an HIV infection.
Chinese scientists use CRISPR on HIV patient for first time
By 2019, there had still not been much direct clinical evidence on whether CRISPR would actually work or be safe to use in people to treat diseases. A group of Chinese scientists were the first to test CRISPR gene editing in a person in 2016, when they injected modified cells that had been edited using CRISPR into a patient with aggressive lung cancer, as part of a clinical trial at the West China Hospital in Chengdu.
It was also Chinese scientists – this time from Peking University – who used CRISPR on an HIV patient for the first time, in 2017. The 27-year-old patient was HIV-positive, and also had acute lymphoblastic leukemia. But researchers offered the man an experimental CRISPR treatment, in an attempt to recreate the experiences of two men known as the Berlin patient and the London patient, in which the men were effectively cured of HIV after receiving stem cell transplants from people born with variations of CCR5, making them highly immune to HIV. As touched upon before, this is because the variation disables a molecular gateway that HIV uses to enter a person’s cells.
In the case of the 27-year-old patient, CRISPR was used to edit the CCR5 gene on bone marrow stem cells taken from a donor, before transplanting the stem cells into the patient. In the paper released in 2019, the Chinese scientists said that “the acute lymphoblastic leukemia was in complete remission and donor cells carrying the ablated CCR5 persisted,” – a full 19 months after the treatment was administered.
However, only around 5% to 8% of the patient’s bone marrow cells carried the CCR5 edit after transplantation, meaning it was not enough for the HIV virus to be eradicated from the patient’s body.
But the lead scientist on the study, Deng Hongkui, told CNN in 2019 that this cannot be seen as a setback. ”The main purpose of the study was to evaluate the safety and feasibility of genetically-edited stem cell transplantation for AIDS treatment,” he said.
In fact, he referred to it as a success because the scientists didn’t detect any gene editing-related adverse events, even if “more long-term in-depth studies are needed for off-target effects and other safety assessments.”
Excision BioTherapeutics: a biotech company on a mission to develop an HIV cure using CRISPR
More recently, in September 2022, it was announced that Excision BioTherapeutics had dosed the first participant in a phase 1/2 trial of its CRISPR-based drug, EBT-101, which is designed to cure HIV infections after a single intravenous infusion. It employs an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and dual guide RNAs, enabling a multiplex editing approach that simultaneously targets three distinct sites within the HIV genome. This allows for the excision of large portions of the HIV genome, thereby minimizing potential viral escape.
EBT-101 is the result of a collaboration between the Lewis Katz School of Medicine at Temple University and Excision – which spun out of Temple. The decision to move the therapy into a clinical trial was bolstered by the success of an analog of the drug, called EBT-001, in rhesus macaques infected with simian immunodeficiency virus (SIV). EBT-001 is identical to EBT-101, except that it uses gRNAs that are specific to SIV sequences. For their preclinical trial, researchers at Temple packaged an SIV-specific CRISPR gene-editing construct that included the Cas9 endonuclease and the guide RNAs into an adeno-associated virus 9 (AAV9) carrier that could be injected intravenously into SIV-infected animals.
The results of the study showed that EBT-001 was broadly distributed throughout the monkeys’ tissue samples, and there was also evidence of edited SIV proviral DNA in their cells and tissues. Additionally, there was no evidence that the drug was toxic at any of the doses tested, and no off-target effects were observed. Ultimately, this was exactly the evidence that Excision needed to secure federal approval to take EBT-101 into human trials.
And, in July this year, Excision received a U.S. Food and Drug Administration (FDA) fast track designation for EBT-101.
There is still a very long way to go for Excision’s CRISPR-based drug candidate, but it could prove to be the best solution for curing HIV if it reaches the finishing line.
What are the challenges in finding a cure for HIV?
HIV brings with it multiple challenges when it comes to finding a cure for the virus. Although there are several approaches that could eventually lead to functional HIV cure, from CRISPR gene editing to immunotherapy, there are plenty of hurdles that need to be overcome in clinical trials, with no investigative ‘cures’ having even reached late-stage clinical testing yet.
One of the biggest challenges around any HIV treatment is the fact that the virus can rapidly mutate and develop resistance. This resistance is caused by changes in the genetic structure of HIV that affect the ability of medicines to block the replication of the virus. In fact, according to WHO, all antiretroviral drugs, including those from newer drug classes, are at risk of becoming partially or fully inactive due to the emergence of drug-resistant virus.
Furthermore, turning our attention back to CRISPR, it is worth noting that it comes with safety concerns, including off-target consequences. This means that an extremely cautionary approach must be taken during clinical trials for CRISPR-based HIV therapies, and long-term studies are a necessity to assess the possibility of any long-term side effects; off-target consequences of CRISPR could take years to become apparent.
Therefore, a CRISPR-based therapy could take a very long time to reach the market and become widely available to the millions of people living with the disease. However, if it does eventually prove successful, it could certainly be one of the most promising solutions for developing a curative treatment for HIV.