Nanozyme 1, Hepatitis C 0: World Hepatitis

Nanozyme 1, Hepatitis C 0: World Hepatitis

GAINESVILLE, Fla. — University of Florida researchers have moved a step closer to treating diseases on a cellular level by creating a tiny particle that can be programmed to shut down the genetic production line that cranks out disease-related proteins.

In laboratory tests, these newly created “nanorobots” all but eradicated hepatitis C virus infection. The programmable nature of the particle makes it potentially useful against diseases such as cancer and other viral infections.

The research effort, led by Y. Charles Cao, a UF associate professor of chemistry, and Dr. Chen Liu, a professor of pathology and endowed chair in gastrointestinal and liver research in the UF College of Medicine, is described online this week in the Proceedings of the National Academy of Sciences.

“This is a novel technology that may have broad application because it can target essentially any gene we want,” Liu said. “This opens the door to new fields so we can test many other things. We’re excited about it.”

During the past five decades, nanoparticles — particles so small that tens of thousands of them can fit on the head of a pin — have emerged as a viable foundation for new ways to diagnose, monitor and treat disease. Nanoparticle-based technologies are already in use in medical settings, such as in genetic testing and for pinpointing genetic markers of disease. And several related therapies are at varying stages of clinical trial.

The Holy Grail of nanotherapy is an agent so exquisitely selective that it enters only diseased cells, targets only the specified disease process within those cells and leaves healthy cells unharmed.

To demonstrate how this can work, Cao and colleagues, with funding from the National Institutes of Health, the Office of Naval Research and the UF Research Opportunity Seed Fund, created and tested a particle that targets hepatitis C virus in the liver and prevents the virus from making copies of itself.

Hepatitis C infection causes liver inflammation, which can eventually lead to scarring and cirrhosis. The disease is transmitted via contact with infected blood, most commonly through injection drug use, needlestick injuries in medical settings, and birth to an infected mother. More than 3 million people in the United States are infected and about 17,000 new cases are diagnosed each year, according to the Centers for Disease Control and Prevention. Patients can go many years without symptoms, which can include nausea, fatigue and abdominal discomfort.

Current hepatitis C treatments involve the use of drugs that attack the replication machinery of the virus. But the therapies are only partially effective, on average helping less than 50 percent of patients, according to studies

published in The New England Journal of Medicine and other journals. Side effects vary widely from one medication to another, and can include flu-like symptoms, anemia and anxiety.

Cao and colleagues, including graduate student Soon Hye Yang and postdoctoral associates Zhongliang Wang, Hongyan Liu and Tie Wang, wanted to improve on the concept of interfering with the viral genetic material in a way that boosted therapy effectiveness and reduced side effects.

The particle they created can be tailored to match the genetic material of the desired target of attack, and to sneak into cells unnoticed by the body’s innate defense mechanisms.

Recognition of genetic material from potentially harmful sources is the basis of important treatments for a number of diseases, including cancer, that are linked to the production of detrimental proteins. It also has potential for use in detecting and destroying viruses used as bioweapons.

The new virus-destroyer, called a nanozyme, has a backbone of tiny gold particles and a surface with two main biological components. The first biological portion is a type of protein called an enzyme that can destroy the genetic recipe-carrier, called mRNA, for making the disease-related protein in question. The other component is a large molecule called a DNA oligonucleotide that recognizes the genetic material of the target to be destroyed and instructs its neighbor, the enzyme, to carry out the deed. By itself, the enzyme does not selectively attack hepatitis C, but the combo does the trick.

“They completely change their properties,” Cao said.

In laboratory tests, the treatment led to almost a 100 percent decrease in hepatitis C virus levels. In addition, it did not trigger the body’s defense mechanism, and that reduced the chance of side effects. Still, additional testing is needed to determine the safety of the approach.

Future therapies could potentially be in pill form.

“We can effectively stop hepatitis C infection if this technology can be further developed for clinical use,” said Liu, who is a member of The UF Shands Cancer Center.

The UF nanoparticle design takes inspiration from the Nobel prize-winning discovery of a process in the body in which one part of a two-component complex destroys the genetic instructions for manufacturing protein, and the other part serves to hold off the body’s immune system attacks. This complex controls many naturally occurring processes in the body, so drugs that imitate it have the potential to hijack the production of proteins needed for normal function. The UF-developed therapy tricks the body into accepting it as part of the normal processes, but does not interfere with those processes.

“They’ve developed a nanoparticle that mimics a complex biological machine — that’s quite a powerful thing,” said nanoparticle expert Dr. C. Shad Thaxton, an assistant professor of urology at the Feinberg School of Medicine at Northwestern University and co-founder of the biotechnology company AuraSense LLC, who was not involved in the UF study. “The promise of nanotechnology is extraordinary. It will have a real and significant impact on how we practice medicine.”

RNA interference is a fundamental gene regulatory mechanism that is mediated by the RNA-induced silencing complex (RISC). Here we report that an artificial nanoparticle complex can effectively mimic the function of the cellular RISC machinery for inducing target RNA cleavage. Our results show that a specifically designed nanozyme for the treatment of hepatitis C virus (HCV) can actively cleave HCV RNA in a sequence specific manner. This nanozyme is less susceptible to degradation by proteinase activity, can be effectively taken up by cultured human hepatoma cells, is nontoxic to the cultured cells and a xenotransplantation mouse model under the conditions studied, and does not trigger detectable cellular interferon response, but shows potent antiviral activity against HCV in cultured cells and in the mouse model. We have observed a more than 99% decrease in HCV RNA levels in mice treated with the nanozyme. These results show that this nanozyme approach has the potential to become a useful tool for functional genomics, as well as for combating protein-expression-related diseases such as viral infections and cancers.

Key facts

Hepatitis C is a liver disease caused by the hepatitis C virus.

The disease can range in severity from a mild illness lasting a few weeks to a serious, lifelong condition that can lead to cirrhosis of the liver or liver cancer.

The hepatitis C virus is transmitted through contact with the blood of an infected person.

About 150 million people are chronically infected with hepatitis C virus, and more than 350 000 people die every year from hepatitis C-related liver diseases.

Hepatitis C is curable using antivirals.

There is currently no vaccine for hepatitis C; however, research in this area is ongoing.

Hepatitis C is a contagious liver disease that results from infection with the hepatitis C virus. It can range in severity from a mild illness lasting a few weeks to a serious, lifelong illness.

The hepatitis C virus is usually spread when blood from an infected person enters the body of a susceptible person. It is among the most common viruses that infect the liver.

Every year, 3–4 million people are infected with the hepatitis C virus. About 150 million people are chronically infected and at risk of developing liver cirrhosis and/or liver cancer. More than 350 000 people die from hepatitis C-related liver diseases every year.

Geographical distribution

Hepatitis C is found worldwide. Countries with high rates of chronic infection are Egypt (22%), Pakistan (4.8%) and China (3.2%). The main mode of transmission in these countries is attributed to unsafe injections using contaminated equipment.

Transmission

The hepatitis C virus is most commonly transmitted through exposure to infectious blood. This can occur through:

receipt of contaminated blood transfusions, blood products and organ transplants;

injections given with contaminated syringes and needle-stick injuries in health-care settings;

injection drug use;

being born to a hepatitis C-infected mother.

Hepatitis C may be transmitted through sex with an infected person or sharing of personal items contaminated with infectious blood, but these are less common.

Hepatitis C is not spread through breast milk, food or water or by casual contact such as hugging, kissing and sharing food or drinks with an infected person.

Symptoms

The incubation period for hepatitis C is 2 weeks to 6 months. Following initial infection, approximately 80% of people do not exhibit any symptoms. Those people who are acutely symptomatic may exhibit fever, fatigue, decreased appetite, nausea, vomiting, abdominal pain, dark urine, grey-coloured faeces, joint pain and jaundice (yellowing of skin and the whites of the eyes).

About 75-85 % of newly infected persons develop chronic disease and 60–70% of chronically infected people develop chronic liver disease; 5–20% develop cirrhosis and 1–5% die from cirrhosis or liver cancer. In 25 % of liver cancer patients, the underlying cause is hepatitis C.

Diagnosis

Diagnosis of acute infection is often missed because a majority of infected people have no symptoms. Common methods of antibody detection cannot differentiate between acute and chronic infection. The presence of antibodies against the hepatitis C virus indicates that a person is or has been infected. The hepatitis C virus recombinant immunoblot assay (RIBA) and hepatitis C virus RNA testing are used to confirm the diagnosis.

Diagnosis of chronic infection is made when antibodies to the hepatitis C virus are present in the blood for more than six months. Similar to acute infections, diagnosis is confirmed with an additional test. Specialized tests are often used to evaluate patients for liver disease, including cirrhosis and liver cancer.

Getting tested

Early diagnosis can prevent health problems that may result from infection and prevent transmission to family members and other close contacts. Some countries recommend screening for people who may be at risk for infection.

These include:

people who received blood, blood products or organs before screening for hepatitis C virus was implemented, or where screening was not yet widespread;

current or former injecting drug users (even those who injected drugs once many years ago);

people on long-term hemodialysis;

health-care workers;

people living with HIV;

people with abnormal liver tests or liver disease;

infants born to infected mothers.

Treatment

Hepatitis C does not always require treatment. There are 6 genotypes of hepatitis C and they may respond differently to treatment. Careful screening is necessary before starting the treatment to determine the most appropriate approach for the patient.

Combination antiviral therapy with interferon and ribavirin has been the mainstay of hepatitis C treatment. Unfortunately, interferon is not widely available globally, it is not always well tolerated, some virus genotypes respond better to interferon than others, and many people who take interferon do not finish their treatment. This means that while hepatitis C is generally considered to be a curable disease, for many people this is not a reality.

Scientific advances have led to the development of new antiviral drugs for hepatitis C, which may be more effective and better tolerated than existing therapies. Two new therapeutic agents telaprevir and boceprevir have recently been licensed in some countries. Much needs to be done to ensure that these advances lead to greater access and treatment globally.

Prevention

Primary prevention

There is no vaccine for hepatitis C. The risk of infection can be reduced by avoiding:

unnecessary and unsafe injections;

unsafe blood products;

unsafe sharps waste collection and disposal;

use of illicit drugs and sharing of injection equipment;

unprotected sex with hepatitis C-infected people;

sharing of sharp personal items that may be contaminated with infected blood;

tattoos, piercings and acupuncture performed with contaminated equipment.

Secondary and tertiary prevention

For people infected with the hepatitis C virus, WHO recommends:

education and counseling on options for care and treatment;

immunization with the hepatitis A and B vaccines to prevent coinfection from these hepatitis viruses to protect their liver;

early and appropriate medical management including antiviral therapy if appropriate; and

regular monitoring for early diagnosis of chronic liver disease.

WHO response

WHO is working in the following areas to prevent and control viral hepatitis:

raising awareness, promoting partnerships and mobilizing resources;

evidence-based policy and data for action;

prevention of transmission; and

screening, care and treatment.

WHO also organizes World Hepatitis Day on 28 July every year to increase awareness and understanding of viral hepatitis.

Source : http://www.who.int/mediacentre/factsheets/fs164/en/index.html

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