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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Nov 14, 2013

 

Gene therapy is not without risks. If integrated too near a carcinogenic gene,
the newly introduced genetic material can also induce disease-causing mutations.

Image Credit: Cell Reports







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Retrofitted protein opens door for safer gene therapy

A protein engineered by scientists combines proteins active in HIV and Moloney murine leukaemia virus (MLV) and may lead to safer, more effective retroviral gene therapy.

The retrofitted protein opens the door for safer gene therapy. This 'fusion' protein could lead to safer, more effective retroviral gene therapy.


Gene therapy involves inserting healthy genetic material into a diseased cell. Using a carrier derived from a retrovirus, the genetic material is smuggled into a human cell where, once inside, it integrates itself into the cell’s DNA.

But gene therapy is not without risks. If integrated too near a carcinogenic gene, the newly introduced genetic material can also induce disease-causing mutations.


In gene therapy, the delivery vehicle is not the retrovirus itself, but a version of the retrovirus that retains its proteins but not its DNA. One of the most widely used viral vectors is derived from MLV. But this particular virus-borne carrier is both a weapon and a risk. It can cure disease but, if inscribed in the wrong place in a cell’s DNA, it can also cause leukaemia.

A separate protein, which plays a role in HIV, does not have that problem. It only integrates itself in ‘safe’ places in the host cell’s DNA.


The researchers put one and two together to create a safer viral vector. Dr. Rik Gijsbers explains:

“We developed a fused protein with the head of the protein that HIV uses and the tail of the protein that MLV uses.”


Writing in Cell Reports, the researchers say their retrofitted retroviral vector works: “Our experiments with cell cultures show that in the presence of this protein, the viral vector always inscribes itself in a safe place, just as it does in the HIV virus,” says Dr. Gijsbers.

Several years ago, scientists successfully used viral vectors derived from MLV to treat a congenital immune system abnormality in children. Some of these children later developed leukaemia. “In these cases, the viral vector embedded itself near a carcinogenic gene,” explains Professor Zeger Debyser, the corresponding author. “This disrupts the gene and leads to a higher leukaemia risk – a serious setback for gene therapy. It put a heavy damper on gene therapy’s future development.”

Until recently, it was not known how or why retroviruses inscribed themselves near cancer genes. Research by the Molecular Virology and Gene Therapy research group at KU Leuven sheds new light on this enigma. Their previous research into HIV proved essential, says Dr. Jan De Rijck: “In 2003, we discovered that HIV uses a particular protein as an anchor to embed itself into the host cell. We asked ourselves whether MLV used a different protein in a similar way, and that was indeed the case. The BET (bromodomain and extraterminal, eds.) proteins we found are the anchors of MLV.” This discovery led the KU Leuven researchers to develop the fusion protein.

Though the initial results are promising, more research is needed to refine them, says Dr. Gijsbers. “But this definitely opens new avenues in the search for a new generation of safe viral vectors in gene therapy, particularly for various blood diseases.”

Abstract Highlights
The BET ET domain specifically interacts with the MLV integrase C terminus
BET chromatin binding inhibitors block MLV replication at the integration step
MLV integration site distribution correlates with the BET chromatin binding profile
MLV vector integration can be retargeted by engineered BET proteins

Summary
A hallmark of retroviral replication is integration of the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in gene therapeutic trials, caused by activation of proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) and MLV integrase specifically interact and colocalize within the nucleus of the cell. Inhibition of the BET proteins’ chromatin interaction via specific bromodomain inhibitors blocks MLV virus replication at the integration step. MLV integration site distribution parallels the chromatin binding profile of BET proteins, and expression of an artificial fusion protein of the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75 retargets MLV integration away from transcription start sites and into the body of actively transcribed genes, conforming to the HIV integration pattern. Together, these data validate BET proteins as MLV integration targeting factors.

Authors
Jan De Rijck, Christine de Kogel, Jonas Demeulemeester, Sofie Vets, Sara El Ashkar, Nirav Malani, Frederic D. Bushman, Bart Landuyt, Steven J. Husson, Katrien Busschots, Rik Gijsbers, Zeger Debysersend emailSee Affiliations


Original press release: http://www.kuleuven.be/english/news/redesigned-hiv-mlv-anchor-opens-door-for-safer-gene-therapy