Can we recreate the Berlin Patient using gene therapy?

03.04.2014
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In 2008, a man known as the Berlin Patient was deemed functionally cured of HIV. This followed receiving an allogeneic stem cell transplant from a donor with an HIV-resistance mutation.

Unfortunately, transplant incompatibility and the rarity of this mutation in the population makes it an unlikely therapy for broad use. Instead, gene therapy shows promise as an alternative method.

In 1995, Timothy Brown was diagnosed with HIV, an infection that was once considered a death sentence, and he was placed with antiretroviral therapy. Then in 2006, he was diagnosed with acute myeloid leukemia that required a stem cell transplant. He didn’t receive just any stem cells though; these were cells were from a donor with a homozygous CCR5 delta32 mutation, which is a rare mutation associated with resistance to HIV. In the years following, his levels of HIV dropped while his CD4 T cell count increased, and he no longer needed to be on therapy to treat his condition. In 2008, this man, also known as the Berlin Patient, was deemed functionally cured of HIV.

Yet, this is just one case. The bigger question is can it be done again?

The problem with the technique is that it requires an allogeneic transplant of cells – from one person to another. The differences in major and minor histocompatibility complexes that are genetically quite diverse within a population often result in either rejection of the transplant by the patient’s immune cells or graft versus host disease if the transplanted immune cells attack the patient’s cells. Finding a close match to avoid these negative effects is challenging.

It’s even less likely to find someone fitting the criteria with the desired CCR5 delta32 mutation making this an unlikely method of treatment for all HIV patients.

This is where gene therapy and Carl June of the University of Pennsylvania come in. In a paper published in October 2013, June’s group along with groups from Albert Einstein College of Medicine in New York and Sangamo BioSciences, reported using zinc-finger nuclease editing to artificially recreate this mutation in T cells resulting in HIV resistance.

Zinc finger nucleases are artificial restriction enzymes containing a zinc finger domain that are designed to recognize and bind to a certain palindromic DNA sequence (the handles of the scissors in the figure below) and a DNA-cleavage domain that can then break the DNA at that position (the blades of the scissors in the figure below). Once they break the DNA, the cell’s repair machinery will then fix the break and by doing so can create a mutation or deletion in that position through homologous or non-homologous end joining.

123a063543fe0297b64a884274570434_m.jpg

These groups took advantage of the specificity these synthetic enzymes by designing one that recognizes around and cleaves at the 32 position of CCR5 to create the HIV-resistance mutation as well as one that targeted a homolog of CCR5, CXCR4. In their 2013 report, they showed that using these enzymes, they can create T cells resistant to HIV that when adoptively transferred to a humanized mouse model of HIV-1 infection, maintain a higher CD4 T cell level than controls. Seeing as a low ratio of CD4 to CD8 T cells is a characteristic of HIV infection, this is able to bring it in the right direction.

This success in a mouse model then brought them to testing their method with humans, and in March 2014, they reported to the New England Journal of Medicine that they completed a phase I trial. The benefit of this technique is that they can isolate a person’s own cells, modify them, and return them to their body meaning the transplanted cells will have the same major and minor histocompatibility complexes as the recipient so no rejection or graft versus host disease should occur. The only difference these cells should have from the patient is that they have mutations making them resistant to HIV infection.

In their clinical trial, June et al. administered such modified cells back into 12 HIV positive patients. This resulted in decreased viral loads of some patients, even those taken entirely off of retroviral drugs. It also led to increased resistance to infection.

As Carl June said in a news release, “This reinforces our belief that modified T cells are the key that could eliminate the need for lifelong [Antiretroviral Drug Therapy] and potentially lead to functionally curative approaches for HIV/AIDS.”

Further clinical trials are in the process to assess this method’s efficacy in a larger cohort as well as to increase the persistence of these transplanted cells.

 

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Image: "Scissor Cut" by Hanna Erickson - Flickr | License: CC By 2.0

Image copyright: NIAID / flickr

Article last time updated on 04.04.2014.

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