Drug: NUC B100
Manufacturer: Nucleonics Inc. (PA, USA)
Stage of development Phase 1 clinical trial
Indication: Chronic HBV infection
NUC B1000, a novel expressed iRNA (eiRNA) product developed by Nucleonics Inc. (PA, USA), has entered a Phase I clinical trial in patients with chronic HBV infection.
HBV infects approximately a third of the world’s population at one point in life. Adults can recover from HBV infection, while infants usually become chronic carriers. Chronic HBV infection can gradually lead to liver damage and is the leading cause of liver cancer.
“Despite the widespread availability of multiple prophylactic vaccines against HBV, chronic HBV infection remains a public health problem around the world that can lead to such serious diseases as cirrhosis, fibrosis and liver cancer in up to one third of patients,” said the principal investigator, Robert Gish of California Pacific Medical Center (CA, USA). “Current anti-HBV drug therapies are of limited effectiveness and are not often used in patients with mild-to-moderate disease due to risks of developing drug resistance. Thus, there is significant need for new treatments that can improve patient response rates to therapy and prevent the emerging drug resistance associated with the use of conventional antiviral therapeutics, enabling more patients to benefit from treatment.”
RNA interference is a process in which gene expression is disrupted by small fragments of RNA that bind complementarily to the mRNA. Since this occurs at the mRNA level instead of gene level, RNA interference is also called post-transcriptional gene silencing. RNA interference has been found in plants, fungi and many animals and is thought to be a natural defense mechanism against viruses.
NUC B1000 contains a plasmid DNA formulated with a proprietary cationic lipid delivery system. The plasmid DNA can transcript into four siRNA molecules, each of which binds to and interferes with a different sequence of the HBV genome. As a consequence, viral RNAs are disrupted and cannot express viral proteins, leading to inhibition of viral replication and spreading. Unlike other antiviral drugs, NUC B1000 can be effective against drug-resistant HBV strains as it works at the mRNA level instead of the protein level. It can reduce the viral RNA and antigen titers, hence reducing the hepatitis effects on the liver and assisting resolution of HBV infection.
In this clinical trial, 15 patients with mild-to-moderate HBV infection and without cirrhosis will be recruited at three sites in the USA and two sites in Eastern Europe. Five groups of three patients will be given five escalating doses of NUC B1000. The new drug will be assessed for its safety (primary end point) and efficacy in reducing HBV load in blood (secondary end point). The trial will be overseen by an independent safety monitor as well as a data safety monitoring board, and preliminary safety data will be analyzed after completion of the third dose group before proceeding to the fourth and fifth groups.
“We are very pleased to initiate this clinical study, which represents one of the first systemic administrations of any RNAi-based therapeutic and is the first RNA interference treatment directed against HBV,” said Robert Towarnicki, president and chief executive officer of Nucleonics Inc. “We believe Nucleonics’ eiRNA approach offers several major advantages over other RNA interference approaches. Each eiRNA molecule entering the nucleus of a targeted cell produces thousands of copies of siRNA, and allows for a sustained therapeutic response versus the repeat administration expected to be required for synthetically created RNA-interference drugs. Moreover, one eiRNA drug molecule has the potential to encode four or more different siRNAs, enabling the attack of multiple targets using a single therapeutic, thereby decreasing the chances of developing drug resistance. Moreover, plasmid DNA is nonimmunogenic and a stable drug format that benefits from well-characterized manufacturing methods, storage techniques, regulatory requirements and the likelihood of a favorable safety profile based on earlier DNA vaccine clinical trials.”
Source: Nucleonics Inc. (PA, USA): www.nucleonicsinc.com
Promising new drug class for toxoplasmosis
In a report published in the January issue of the journal Nature, blocking the production of abscisic acid (ABA) in Toxoplasma gondii using low dose of a herbicide could prevent fatal infection in mice.
Cats are natural carriers of the parasitic protozoan T. gondii – the causative agent of toxoplasmosis. Humans can get infected through ingestion of spores, although the infection is usually asymptomatic or mild with influenza-like symptoms and is self-limiting. However, toxoplasmosis is especially dangerous to the human fetus as it can cause stillbirth or fatal defects; therefore, pregnant women should avoid changing cat litter that may contain T. gondii spores.
T. gondii and other protozoan parasites, such as Plasmodium species (causing malaria), contain a number of genes derived from plants, which are thought to be acquired from an algal cell millions of years ago. ABA is a plant hormone involved in regulation of flowering and seed dormancy. In the parasites, ABA has been shown to serve as a signaling molecule in communicating between cells and controlling their reproductive cycle.
“As a target for drug development, this pathway is very attractive for several reasons,” says the lead author David Sibley of Washington University in St Louis School of Medicine (MO, USA). “For example, because of its many roles in plant biology, we already have several inhibitors for it. Also, the plant-like nature of the target decreases the chances that blocking it with a drug will have significant negative side effects in human patients.”
There have been publications reporting the use of antiparasitic drugs that block plant-like molecules used by parasites in metabolic pathways. However, this is the first study demonstrating a similar drug that can inhibit a signaling pathway of parasites.
“Signals are sometimes even better targets for drug development than biosynthetic pathways,” commented Sibley. “Taking out a biosynthetic pathway means you take away one thing from the parasite. But if you can successfully disable a key signal, this may potentially disrupt many more aspects of the parasite’s metabolism.”
ABA pathways in T. gondii were discovered previously by Kisaburo Nagamune, the first author of the current study. Using a known herbicide that blocks ABA production, the researchers found that it reduced the number of T. gondii in mice during infection. The next steps are to investigate the effects of other ABA inhibitors on T. gondii and to explore similar drugs in malaria treatment.
Source: Nagamune K, Hicks LM, Fux B, Brossier F, Chini EN, Sible LD. Abscisic acid controls calcium-dependent egress and development in Toxoplasma gondii. Nature 451(7175), 207–210 (2008); Washington University in St Louis School of Medicine, MO, USA: www.wustl.edu
Antivirals prescribed for UK seasonal influenza
The UK Health Protection Agency (HPA) has announced that the circulating rate of seasonal influenza in the UK has reached the threshold at which antiviral drugs are now recommended.
“Vaccination offers the best protection for those at high risk from seasonal influenza and these groups should have been vaccinated by now. Antivirals are only effective if taken within 48 h of onset of symptoms and may help limit the impact of some symptoms and reduce the potential for serious complications. However, it is difficult to avoid infection if there is a lot of flu circulating,” commented John Watson of the HPA.
Influenza symptoms include headache, fever, coughing, sore throat and body aches. Seasonal influenza vaccines are available and recommended for those at increased risk of developing complications. Patients are advised to rest, drink plenty of fluid and take pain killers until the disease resolves itself.
“Our surveillance shows that since mid December this year (2007), seasonal flu activity has started to increase to normal seasonal levels that the National Institute for Health and Clinical Excellence guidelines refer to as the level seen most winters,” said Watson. “For most people, flu is miserable, lasting a week or so, but not life threatening. For those in at-risk groups, however, such as the elderly and patients with heart problems, diabetes or lung, liver or renal diseases, or those who have weak immune systems, it can be far more dangerous and can lead to more serious illnesses.”
Doctors are now prescribing antiviral drugs for the prevention or treatment of influenza in patients who are at higher risk of developing complications.
Source: UK Health Protection Agency: www.hpa.org.uk
Targeting human proteins may be a new HIV therapeutic approach
New findings of 273 ‘HIV-dependency factors’ in human cells have been published in the January issue of the journal Science.
Although HIV contains only nine genes encoding for 15 proteins, its intrinsic high rate of mutation has been the major hurdle in anti-HIV research. Mutant HIV strains develop antiviral resistance quickly and it is often necessary to use a combination of toxic antivirals in HIV therapy, which leads to increased drug nonadherence in patients and further drug resistance in HIV.
“Antiviral drugs are currently doing a good job of keeping people alive, but these therapeutics all suffer from the same problem, which is that you can get resistance, so we decided to take a different approach centered on the human proteins exploited by the virus,” explained the senior author of the study Stephen Elledge. “The virus would not be able to mutate to overcome drugs that interact with these proteins.”
Using a library of siRNAs, scientists at Harvard Medical School (MA, USA) have screened the whole human genome for genes that HIV relies on to infect host cells. When the expression of these genes was inhibited individually by corresponding siRNAs, HIV could not replicate and spread normally.
‘These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle,’ wrote the authors. Only 36 out of the 273 identified proteins have been reported previously to be involved in HIV replication.
“This is the first whole-genome screen for human proteins required by HIV, and we are confident that it netted real results,” commented the first author of the study, Abraham Brass. “Given the method, we missed some proteins, but the majority of the ones we found are highly likely to play a role in HIV propagation.”
The new list opens new avenues in the development of potential drugs that target human proteins instead of HIV. “Scientists can look at the list, predict why HIV needs a particular protein, and then test their hypothesis,” said Elledge. “We might be able to tweak various parts of the system to disrupt viral propagation without making our own cells sick.”
Source: Brass AL, Dykxhoorn DM, Benita Y et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science DOI: 10.1126/science.1152725 (2008) (Epub ahead of print).
H5N1 avian influenza virus in swans in Dorset
Following a routine surveillance program, three dead wild mute swans were found and tested positive with the H5N1 avian influenza virus by the UK Veterinary Laboratories Agency. Wild bird control and monitoring areas have been set up around Chesil Beach and Portland Bill in Dorset.
Bird keepers within these areas are required to isolate their birds from contact with wild birds. No disease has been found in domestic birds and there will be no culling of wild birds as this may affect wild bird movement and control. The UK Department for Environment, Food and Rural Affairs is working with ornithological and other experts to see what other measurements are necessary.
“While this is obviously unwelcome news, we have always said that Britain is at a constant low level of risk of introduction of avian influenza. Our message to all bird keepers, particularly those in the area, is that they must be vigilant, report any signs of disease immediately and practice the highest levels of biosecurity,” said the acting chief veterinary officer Fred Landeg.
All poultry keepers in the UK, as well as the European Union Commission have been informed. An epidemiological investigation is being carried out.
Source: UK Department for Environment, Food and Rural Affairs: www.defra.gov.uk
Dengue may be a potential threat to US public health
In the January issue of the Journal of the American Medical Association, Anthony Fauci and David Morens of the US NIH’s National Institute of Allergy and Infectious Diseases (NIAID) have warned that dengue may pose a potential threat to US public health.
Dengue is caused an arbovirus that is transmitted by the mosquitoes Aedes albopictus and Aedes aegypti. Most infections are asymptomatic or with mild fever, although high fever, headache, muscle and joint pains and minor bleeding in gums or nose can be present in more serious cases. In severe cases, blood leakage from the circulation into surrounding tissues can occur, leading to loss of blood pressure, shock and even death if left untreated. The WHO defines severe forms of dengue as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).’
As the dengue virus is dependent on the mosquito hosts, dengue is confined within tropical/subtropical regions where the mosquitoes can reproduce. However, with global climate change, the mosquito species known to carry the dengue virus has appeared in many, mostly southern, states of the USA. The disease occurs sporadically and so far has not had a major impact in public health. However, ‘widespread appearance of dengue in the continental United States is a real possibility,’ wrote the authors. ‘Worldwide, dengue is among the most important re-emerging infectious diseases with an estimated 50 to 100 million annual cases … (and) 22,000 deaths.
In 2007, the NIAID allocated US$33.2 million for almost 60 research projects on dengue, including basic research, DHF and DSS, diagnostics and therapeutics for the disease and vaccine development. Priorities set by the NIAID are development of suitable animal models, assessment of new vaccines and drugs, understanding the pathogenesis of DHF and DSS, and finding predisposing factors that may put individuals at risk of contracting dengue.
Source: Morens DM, Fauci AS. Dengue and hemorrhagic fever: a potential threat to public health in the United States. JAMA 299(2), 214–216 (2008); US National Institute of Allergy and Infectious Diseases: www.niaid.nih.gov