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Of Mice Not Men: Tracking mosquito viruses; CRISPR-ing obesity and tumors


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Of Mice Not Men: Tracking mosquito viruses; CRISPR-ing obesity and tumors

This is a recurring column on early-stage research in animals or other laboratory models that has not entered the clinic yet but could have implications for future research and development of human medicines.

Monitoring viruses in mosquitoes

Researchers at the University of Missouri are following the movement of viruses in mosquitoes, with the help of electron microscopes. In doing so, the researchers may be able to determine the genes involved in the transmission of the virus.

The study, which is part of a doctoral project, used three electron microscopes to observe the stomach of a mosquito infected with the chikungunya virus. Altogether, the microscopes provided a three-dimensional view of the stomach's tissue and allowed the research team to track the movement of the virus. According to the observations, the virus particles left the stomach within 48 hours.

"Previously, the common understanding was that when a mosquito has picked up a virus, it first needs some time to build up inside the midgut, or stomach, before infecting other tissues in the mosquito," University of Missouri assistant professor of veterinary pathobiology Alexander Franz said. "In fact, there is only a narrow window of 32 to 48 hours between the initial infection and the virus leaving the mosquito's stomach … That revelation is eye-opening."

Alzheimer's protein amyloid may spread like prion protein

The amyloid protein, which builds up in the brain during Alzheimer's disease and is believed to play a central role in the condition, may spread through contaminated brain tissue extracts, according to research in mice.

The study, conducted by University College London scientists, compared the transmission process to that of the prion protein, which characterizes the brain disease Creutzfeldt-Jakob disease, or CJD. The scientists had previously found that eight people who developed CJD had received human-derived growth hormone before the mid-1980s. The prion protein was found in all eight people, and four out of the eight also had unusually high levels of amyloid in their brains' tissue and blood vessels.

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The team detected amyloid in the original samples of the growth hormone. Thus, the researchers injected the growth hormone into mice that had been genetically modified to be more susceptible to amyloid build-up. After 240 days, the mice injected with the growth hormone samples had significantly higher levels of amyloid in their brains compared to mice injected with control samples without amyloid.

Though amyloid build-up, called cerebral amyloid angiopathy, is linked to Alzheimer's, whether it directly causes the disease remains to be seen, according to Alzheimer's Research UK chief scientific officer David Reynolds.

"Although the findings might sound concerning, strict guidelines surrounding the sterilization and use of surgical equipment have already been introduced since the discovery of prion protein contamination and CJD," Reynolds said. "Importantly, there remains no evidence of Alzheimer's disease being transmitted through blood transfusions and further work to understand the mechanics of amyloid transmission is ongoing."

Using CRISPR to target obesity

A research team at University of California, San Francisco has found that a modified version of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR, technology can be used to prevent severe obesity in mice.

According to their study, the modified CRISPR mechanism, dubbed CRISPRa, or CRISPR activation, did not edit any genes, but rather targeted certain sequences that regulate activity of genes commonly associated with obesity. The genes, SIM1 and MC4R, regulate hunger and satiety. Mutations in a copy of either gene leave behind only one working copy, which can lead to severe obesity.

CRISPRa was delivered via injection to mice that had been genetically modified to have only one working copy of either SIM1 or MC4R. Those that received the injections had SIM1 or MC4r activity comparable to regular mice that had not been genetically modified; and the CRISPRa-treated mice were 30% to 40% lighter than genetically modified mice that had not received the injections. At 10 months, a significant period of time in a mouse's lifespan, the treated mice had maintained a healthy weight.

The researchers noted that CRISPRa could have an advantage over conventional CRISPR gene editing because CRISPRa targets promoters and enhancers, which are noncoding DNA sequences that control gene activity, and therefore, any unintended consequences would potentially be less severe. CRISPRa may even prevent off-target effects, according to the study. Off-target effects have been observed from traditional CRISPR gene editing, lending the technology to further debate and controversy.

"Though this particular study focused on obesity, we believe our system could be applied to any situation in which having only one functional copy of a gene leads to disease," senior author of the study Nadav Ahituv said. "Our method demonstrates tremendous therapeutic potential for numerous diseases, and we show that we can achieve these benefits without making any edits to the genome."

CRISPR-ing chemotherapy resistance in lung cancer

In other CRISPR news, scientists from the Gene Editing Institute at Delaware's Christiana Care Health System used traditional CRISPR-Cas9 gene editing to modify chemotherapy-resistant genes in lung cancer tumors and enhance the treatment's effectiveness.

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The study was conducted in tissue culture and a mouse, and used CRISPR-Cas9, which edits a DNA sequence by cutting out and altering a section, to disable a tumor gene called NRF2. In lung cancer tumors, NRF2 controls cell functions that give rise to chemotherapy resistance.

The tissue culture and mouse both saw a halt in tumor growth for 16 days, as well as tumor reduction when given the CRISPR-Cas9 therapy with chemotherapy.

According to the study's principal author and director of the Gene Editing Institute Eric Kmiec, this tumor gene approach does not directly impact a patient's DNA.

"We think it's best to start with CRISPR therapies that involve relatively conservative uses of this powerful tool," Kmiec said. "This approach can also hopefully help contain costs and provide a level of safety and reliability that is reassuring for patients and increases the chance that insurance companies will provide coverage."