Scientists Discover Potential Pathway of LRRK2 Dysfunction.


Researchers from Johns Hopkins University have reported on a potential route through which mutations in the LRRK2 gene — the greatest known genetic contributor to Parkinson’s disease (PD) — lead to cell death. This finding comes as much of the PD research field, including many initiatives from The Michael J. Fox Foundation, is tuned to discover more about the biology of theLRRK2 gene and its corresponding protein, a potential target of disease-modifying therapies.

Husband and wife Ted Dawson, MD, and Valina Dawson, PhD, led the study, partially funded by the National Institutes of Health, and recently published in Cell. MJFF did not fund this study, but has supported the work of both before.

They found that mutations in the LRRK2 gene may increase the rate at which the LRRK2 protein modifies ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.

Experiments suggested that mutations in LRRK2 increase the rate at which it modifies two ribosomal proteins, called s11 and s15. Further tests showed that increased s15 activation was associated with cell death and abnormally high levels of all proteins. This action caused by the LRRK2 mutation may cause ribosomes (the cell’s protein-making factories) to make too much protein.

“Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders,” said Dr. Ted Dawson.

He and his colleagues think that blocking excess activation of s15 ribosomal could lead to future therapies and measuring s15 could also act as a biomarker of LRRK2 activity in treatment trials.

MJFF has a LRRK2 Consortium of world-class investigators working to identify substrates of LRRK2 — the proteins that it modifies — to reveal new drug targets and biomarkers. More so toward those goals, the Foundation is gathering data and biosamples from people with and without PD with a LRRK2 mutation through the LRRK2 Cohort Consortium and the Parkinson’s Progression Markers Initiative, two large-scale clinical studies.

 

A Malaria Vaccine Works, With Limits.


A new type of malaria vaccine gave 100 percent protection against infection to a small number of volunteers in recent tests — but under conditions that would be nearly impossible to reproduce in the countries where most malaria victims live.

The vaccine, made by Sanaria, a Maryland company, protected six volunteers who each got five doses over 20 weeks, according to a studypublished last week in Science.

But the vaccine is expensive to make and difficult to administer, and it is not yet clear how long the protection lasts.

“This is a scientific advance rather than a practical one,” said Dr. William Schaffner, the head of preventive medicine at Vanderbilt University’s medical school. “But any vaccine that provides even a glimmer of hope opens a door, so we have to pursue it.”

Sanaria’s vaccine is made by irradiating mosquitoes that have fed on malaria-infected blood and removing their salivary glands by hand. The radiation-weakened parasites in the saliva are then purified.

In earlier trials, the vaccine failed when injected into the skin, so this time researchers from the Army, Navy and National Institutes of Health gave it by IV. Six volunteers who got five intravenous doses did not get malaria when bitten by infected mosquitoes. Six of nine volunteers who got four doses were protected.

Because the vaccine is made in small batches by hand, it is impractical for poor countries, where malaria sickens more than 200 million people a year and kills about 660,000, most of them infants and pregnant women.

Giving multiple IV doses of any vaccine is also impractical because it requires sterile conditions, trained medical personnel and follow-up. IVs are particularly hard to administer to children. “They’ve been known to squirm,” Dr. Schaffner noted.

The initial target markets for the vaccine are the military and wealthy travelers.  

Source: http://www.nytimes.com

Zapped malaria parasite raises vaccine hopes.


Maverick malaria vaccine achieves 100% protection using parasites from irradiated mosquitoes.

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A malaria vaccine has become the first to provide 100% protection against the disease, confounding critics and far surpassing any other experimental malaria vaccine tested. It will now be tested further in clinical trials in Africa.

The results are important because they demonstrate for the first time the concept that a malaria vaccine can provide a high level of protection, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, adding that the findings are cause for “cautious optimism”.

No effective malaria vaccine is available at present. The World Health Organization has set a target to develop a malaria vaccine with 80% efficacy by 2025, but until now, says Fauci, “we have not even gotten anywhere near that level of efficacy.”

Scientists had previously been sceptical of the vaccine because producing it required overcoming massive logistical hurdles. The vaccine — called PfSPZ because it is made from sporozoites (SPZ), a stage in the life cycle of the malarial parasite Plasmodium falciparum (Pf) — uses a weakened form of the whole parasite to invoke an immune response.

In the phase I safety trial, reported today in Science1, the six subjects given five doses intravenously were 100% protected from later challenge by bites of infectious mosquitoes, whereas five of six unvaccinated controls developed malaria — as did three of nine people given only four doses of the vaccine.

PfSPZ was developed by Sanaria, a company based in Rockville, Maryland, and led by Stephen Hoffman, a veteran malaria researcher who also led the PfSPZ clinical trial. Most malaria-vaccine candidates are recombinant-subunit vaccines containing just a handful of parasite proteins, but Hoffman decided to test the whole-sporozoite vaccine on the basis of past experiments dating back to the 1970s showing that strong and long-lived protection could be obtained by exposing volunteers to thousands of bites from irradiated infected mosquitoes2.

That the vaccine works so well is a “pivotal success,” says Stefan Kappe, a malaria researcher at the Seattle Biomedical Research Institute in Washington.”The trial results constitute the most important advance in malaria vaccine development since the first demonstration of protection with radiation attenuated sporozoite immunization by mosquito bite in the 70s.”

Against the odds

But to make PfSPZ was challenging. Sanaria succeeded in raising mosquitoes in sterile conditions on an industrial scale, feeding them blood infected with the malaria parasite and then irradiating them to weaken the parasite so that it can still infect people but not cause disease.

Billions of parasites were then harvested from the mosquitoes’ salivary glands, purified and cryopreserved. Many researchers were highly sceptical that sporozoites could be mass-produced in a way that passed the strict quality and safety standards needed for human medicines, notes Fauci. “To my amazement, Hoffman did it,” he adds.

Hoffman says that he hopes to have a vaccine licensed within four years. The trial now needs to be repeated and extended in regions where malaria is rampant to test whether it provides protection against different strains of the parasite than that used in the vaccine, and to see how it performs in different age groups, including young children. The first trials will be carried out at the Ifakara Health Institute in Tanzania.

Piggybacking infrastructure

Even if the vaccine is shown to be highly effective in the field, logistical difficulties might limit its applicability. In mass vaccination campaigns, hundreds of people are vaccinated within minutes, so vaccines are usually given orally or by injection into or just under the skin. Intravenous injection is more cumbersome. “It’s very unlikely to be deployable in infants or young children,” argues Adrian Hill, a malaria researcher at the Jenner Institute in Oxford, UK.

In 2011, a clinical trial of PfSPZ given under the skin reported disappointing results, protecting only two of 80 subjects3. But the need to deliver the vaccine intravenously “is not a show-stopper”, says Hoffman, noting that the volume of vaccine —  0.5 millilitres — is tiny and requires a tiny syringe, although the company is exploring ways to improve the intravenous delivery system.

Another logistical hurdle, says Hill, is that the vaccine must be kept frozen in liquid nitrogen vapour phase. Hoffman argues, however, that the vaccine can piggyback on veterinary infrastructure in places that use liquid nitrogen to store and transport veterinary vaccines and semen for artificial insemination of livestock. “If you can carry semen into the deep Saharan belt and remote areas, why can’t you do that for a human vaccine?” says Marcel Tanner, director of the Swiss Tropical and Public Health Institute in Basel, Switzerland, which is a sponsor of the trial in Tanzania.

“Which of the logistical challenges can be managed and which will become show-stoppers can be difficult to predict,” says David Kaslow, director of the PATH Malaria Vaccine Initiative in Washington, DC, a public–private partnership for malaria-vaccine development.

Kappe hopes the trial results will encourage funders to invest more in optimizing this vaccine approach. “If we were talking about an HIV vaccine, there would be no question about investing in this type of success,” he says.

Source: Nature

Patient Caught Rabies Through Organ Transplant, CDC Says.


A patient who recently died of rabies in Maryland contracted the illness from a kidney transplant received over a year ago, the CDC reported on Friday. The lengthy incubation period, while longer than the typical 1 to 3 months, is unusual but not unprecedented.

Tests on tissue samples from the patient and donor confirmed that they were both infected with raccoon-type rabies. The three other patients who received organs from the donor have been identified and are receiving anti-rabies shots.

The CDC notes: “If rabies is not clinically suspected [in a potential donor], laboratory testing for rabies is not routinely performed, as it is difficult for doctors to confirm results in the short window of time they have to keep the organs viable for the recipient.”

Source: CDC

Aspergillus Meningitis Linked to Steroid Injections Sickens 26, Kills 4 .


Twenty-six patients have contracted fungal meningitis after receiving spinal steroid injections for back pain, CNN reports. Four of the patients have died.

The majority of cases — 18 — have occurred in Tennessee; the rest are divided among Florida, Maryland, North Carolina, and Virginia.

Clinicians suspect that the steroid, preservative-free methylprednisolone acetate, was contaminated with the fungus Aspergillus. All patients received injections between July 1 and September 20, and with the incubation period lasting as long as 4 weeks, more cases may still be identified.

The New England Compounding Center, which has been implicated in the outbreak, has recalled three lots of methylprednisolone acetate: #05212012@68, #06292012@26, and #08102012@51.

Asked to comment, Journal Watch‘s Paul Sax said: “What makes this [outbreak] notable is both the severity and the rarity of the condition, Aspergillus meningitis. Needless to say, consultation with a specialist in infectious diseases would be highly recommended for any clinician encountering such a case.”

Source: CNN