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Thursday, January 24, 2019

Porphyromonas gingivalis in Alzheimer’s, treatment with small-molecule inhibitors

Abstract

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.
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Euro meds regulator set to move from London on 1 March


The European Medicines Agency (EMA) has officially taken over its new building in Amsterdam in preparation of its move to the Dutch capital from London.
EMA will leave its premises in London on 1 March and relocate to the Spark building in the Sloterdijk area of Amsterdam, its temporary location while a permanent home in the Zuidas business district is completed.
Between 4 and 8 March there will only be a skeleton staff at the site, and the agency will rely on teleworking to keep operating, focusing on priority activities including “the authorisation, maintenance and supervision of medicines,” as well as Brexit preparations.
The remainder of the workforce – now expected to be reduced by around 25% due to staff losses compared to earlier estimates of around 30% – will move into the Spark building during the following week. Prior to the decision to relocate to Amsterdam, the EMA employed around 890 people at its headquarters in Canary Wharf.
The EMA has also published a document explaining its key priorities for 2019, as it will not be able to operate at full capacity during the transition, although it has said drug evaluation activities shouldn’t be affected. Key activities will include maintaining the availability of medicines and antimicrobial resistance, strengthening pharmacovigilance, and supporting “patient focused innovation.”
EMA’s official address, which is the location of the permanent facility, is Domenico Scarlattilaan 6, 1083 HS Amsterdam,  but meetings and visits will take place for the time being at the Spark building, located at Orlyplein 24, 1043 DP Amsterdam.
Meanwhile, the Dutch government has said that hundreds of companies have been in contact about moving to the Netherlands as a result of Brexit, according to an articlein the Independent. The news comes after tech giant Sony said it would relocate its European headquarters to Amsterdam from London.
A spokesman for the Netherlands Foreign Investment Agency (NFIA) said the number of enquiries from UK businesses had risen from 80 at the start of 2017 to 150 a year ago and more than 250 at the last count. Other destinations said to be enjoying an increase in popularity among UK-based businesses are worried about the consequences of Brexit include Dublin, Paris, Luxembourg, and Frankfurt.
The pharma sector has also been affected. Last year, for example, AstraZeneca said it was suspending making any decision about its manufacturing investment plans until there is clarity on the UK’s future trading relationship with the EU after Brexit, while Steris plc said it plans to re-domicile to Ireland as a direct result of the decision to leave the EU.
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Two Back Pain Procedures May Be Useless


Injecting cement into broken vertebrae to stabilize an osteoporosis-related spinal fracture does little to reduce pain and disability, a new report says.
Two surgeries are used for these types of fractures: vertebroplasty, in which medical grade cement is injected into broken vertebrae to fuse the fragments together; and balloon kyphoplasty, where a balloon is inserted into a compressed area of spine to lift it and allow cement to be inserted before the balloon removal.
But vertebroplasty provided no clearly significant benefit in pain control over placebo procedures in five randomized placebo-controlled trials, according to the report by an American Society for Bone and Mineral Research global task force of bone health experts.
It also said there is a lack of placebo-controlled trials for balloon kyphoplasty, and a small number of comparison trials found that kyphoplasty provided no more benefits than vertebroplasty.
The report was published Jan. 24 in the Journal of Bone and Mineral Research.
Each year, about 750,000 Americans suffer compression fractures in their spine caused by osteoporosis. These fractures result in acute and chronic back pain, impaired mobility and disability.
The two types of surgery are aggressively marketed as “noninvasive” ways to get immediate relief from pain and as a way to avoid potential opioid addiction caused by narcotic painkillers.
The report’s message “for doctors and their patients suffering from painful spinal fractures is that procedures to stabilize spinal fractures should not be a first choice for treatment,” said report lead author Dr. Peter Ebeling. He’s head of the Department of Medicine at Monash University in Australia.
“While patients who had these surgeries may have had a short-term reduction in pain, we found that there was no significant benefit over the long term in improving pain, back-related disability and quality of life when compared with those who did not have the procedures,” Ebeling said in a journal news release.
But one back pain specialist noted there may still be a place for the procedures.
If a patient can’t move because of pain from a spinal fracture, bone cement might not be so bad, Dr. Joshua Hirsch, from Massachusetts General Hospital, told the New York Times.
“You have a choice,” Hirsch told the newspaper. “Opiates and lying in bed with diminished activity, or a procedure that can mobilize patients and improve them.”
About 300,000 U.S. patients underwent the procedures between 2006 and 2014, according to Medicare data. Of those, 73 percent had the more expensive balloon cement injection procedure.
As the U.S. population ages, the number of people having the procedures is expected to rise, but this “report makes it clear that these procedures are not a magic bullet,” said Dr. Bart Clarke, president of the American Society for Bone and Mineral Health.
“Until now, doctors have been left to sift through the data on their own to determine whether these procedures can benefit their patients. This report coalesces all that information concisely and provides recommendations to guide them,” said Clarke, co-author of an accompanying editorial in the journal.
The task force report also emphasized the need for prevention. Patients who have had a first fracture of the hip or spine likely have osteoporosis and are likely to experience a second fracture. About 25 percent of older patients who have a hip fracture will have a second fracture within one year, as will around 20 percent of older patients who have a vertebral fracture.
But research shows that treatment rates for hip fracture patients are low and decreasing.
“Overall, prevention is critical and we need to get these high-risk patients on anti-osteoporosis drugs that have proven to reduce future fractures by as much as 70 percent,” Clarke said.
More information
The American Academy of Orthopaedic Surgeons has more on osteoporosis and spinal fractures.
SOURCES: Journal of Bone and Mineral Research, news release, Jan. 24, 2019, New York Times, Jan. 24, 2019
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Connecting Dots Between Heartburn Meds, Kidney Damage


Just because a medication is available over the counter doesn’t mean it won’t have side effects or pose other dangers. One example is PPIs, a popular type of heartburn medication that can harm the kidneys, especially when taken long-term.
Heartburn is the result of stomach acid backing up into the esophagus, the tube that goes from your mouth to your stomach. Weakness in the muscle at its base is often to blame. If it flaps open, acids can rise up, causing a burning feeling in the chest.
More than 15 million Americans use proton pump inhibitors, or PPIs, to treat heartburn, either in prescription or over-the-counter forms, including well-known names like Prevacid, Prilosec and Nexium, according to researchers at Washington University in St. Louis.
While these drugs relieve symptoms fast, they’ve been associated with kidney disease, and the longer you take them, the greater the risk, researchers found. They followed nearly 200,000 people for five years and noted chronic kidney disease in 15 percent of PPI users compared with 11 percent of people who used H2 blockers, another heartburn drug.
PPI users are at a significantly higher risk of kidney failure compared with H2 blocker users, although it’s rare. PPIs have also been associated with bone fractures, infections, vitamin B12 deficiency and even dementia, though the exact links aren’t clear. So if you do need a PPI or even an H2 drug, take it for the shortest time possible.
Occasional heartburn is common, and lifestyle changes may ease the discomfort and the need for medication.
Cooling Off Heartburn
  • Take small, frequent meals, and eat slowly.
  • Stop eating at least three hours before bedtime.
  • Don’t lie down or exercise right after a meal.
  • Raise the head of your bed slightly to create an incline when sleeping.
  • Get rid of tight jeans and other clothing that puts pressure on your gut.
  • Keep a journal to pinpoint foods and beverages that could lead to your heartburn. Possibilities are fatty and spicy foods, chocolate, coffee, tea and soda.
But don’t ignore chronic heartburn. If it occurs more than twice a week, doesn’t respond to short-term use of an antacid such as Rolaids or Tums, or starts to get in the way of everyday life, make an appointment with your doctor. It could be a sign of a more serious health condition.
More information
The American Gastroenterological Association has detailed information on heartburn as well as GERD, a possible source of the discomfort.
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As Opioid Crisis Continues, More Donor Organs Carry Hep C


Add another hardship to the many already triggered by the opioid epidemic: More donated organs infected with the hepatitis C virus.
“The ongoing U.S. opioid crisis has resulted in an increase in drug overdose deaths and acute hepatitis C virus infections, with young persons (who might be eligible organ donors) most affected,” explained a team led by Dr. Winston Abara. He’s a hepatitis researcher at the U.S. Centers for Disease Control and Prevention.
Between 2010 and 2017, the number of organs obtained from so-called “increased risk” donors — people at risk of carrying hepatitis due to behaviors such as drug abuse — tripled, the new study found.
In 2010, about 9 percent of donor organs came from these at-risk individuals, but seven years later that number had already risen to more than 26 percent, Abara’s team reported.
The number of organs obtained from people who died from “drug intoxication” also tripled, from just over 4 percent in 2010 to just over 13 percent by 2017, the CDC researchers said. Organ donor deaths tied to injected drugs (such as heroin), specifically, rose fivefold over the same period, they added.
All of this is cause for concern, since tainted needles are a prime conduit for infection with hepatitis C, which can trigger potentially fatal liver disease over time.
Still, advances in medical care mean that many hepatitis-infected donor kidneys, livers and other organs could be lifesavers for the thousands of Americans on transplant waiting lists.
That’s because powerful new medicines that rid the body of hepatitis C can render the transplant viable, Abara’s group said.
Recipients in need of an organ could be “screened post-transplant and, if hepatitis C infection is diagnosed, offered treatment,” the study authors explained.
Liver specialist Dr. David Bernstein agreed.
“Highly effective, direct-acting antiviral therapies have led to almost universal cure of hepatitis C infection,” noted Bernstein, who is chief of hepatology at Northwell Health in Manhasset, N.Y.
These drugs include powerful, but expensive, medicines — such as Sovaldi (sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) — which can clear hepatitis C from the body in a matter of months.
With more hepatitis-infected organs now in the transplant pipeline, the advent of these drugs has “led to the use of these hepatitis C donor organs being placed into hepatitis C-negative recipients, especially in solid organ transplants such as kidney, heart and liver,” Bernstein said.
Once the recipient receives the infected organ, they are typically given one of these medicines, with “the result being universal cure,” he said. “This has allowed more patients awaiting organ transplantations to receive the lifesaving treatment that they need.”
However, understanding the presence of addiction in a deceased donor’s history, and screening donated organs for hepatitis, remains essential.
With that knowledge in place, “recipients and their clinicians can [then] be notified and patients can be appropriately screened post-transplant,” the CDC team wrote.
The findings were published Jan. 25 in the CDC’s Morbidity and Mortality Weekly Report.
More information
There’s more on organ donation and transplant at organdonor.gov.
SOURCES: David Bernstein, M.D., vice chair, medicine for clinical trials, and chief, hepatology, Northwell Health, Manhasset, N.Y.; Jan. 25, 2019, Morbidity and Mortality Weekly Report
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With Gossamer IPO SEC bypass, Nasdaq charts path for others


  • Nasdaq gave its first public guidance Thursday to companies seeking to go public amid the partial government shutdown, the same week Gossamer Bio became the industry’s first initial public offering to use an unusual legal maneuver to bypass the Securities and Exchange Commission.
  • Typically, companies work back and forth with the SEC to resolve questions about their IPOs. But those reviews stopped when the shutdown began, leaving some companies to consider taking the seldom-used step of modifying their registration statements to side-step the need for clearance from the federal agency.
  • Gossamer Bio did just that in a Wednesday filing, setting up an offering in mid-February that could raise $264.5 million. And on Thursday morning, Nasdaq formalized its approach to the tactic, saying it generally would list companies that have either satisfied the SEC review or who say they have fully addressed all agency comments. Gossamer declined to comment Thursday if it received a clear signal that Nasdaq would list the company.

More biotechs could follow Gossamer’s lead, particularly if resolution to the shutdown remains a distant prospect. But the legal workaround is far from risk-free.
The SEC workaround requires a 20-day waiting period in which the IPO price is fixed, potentially exposing the company to the risk of fluctuations in the broader market. In Gossamer’s case, the registration statement will automatically become effective on Feb. 12, and the company can be listed on an exchange anytime after that.
In its amended registration statement, Gossamer disclosed that relying on the approach could “result in a number of adverse consequences, including the potential for a need for us to file a post-effective amendment and distribute an updated prospectus to investors, or a stop order issued preventing use of the registration statement, and a corresponding substantial stock price decline, litigation, reputational harm or other negative results.”
The clinical-stage biotech declined to elaborate on why it chose this route. Legal experts have told BioPharma Dive that biotechs dependent on additional cash would be most likely to consider the option. Gossamer had $256 million in cash and equivalents as of Sept. 30, 2018, which it estimated as sufficient to run the company for at least 12 months.
The IPO proceeds would help fund anticipated increases to clinical trial expenses for three therapeutic candidates, the company stated. The company also scaled aggressively last year, going from 11 employees in January 2018 to 104 full-time workers by year’s end.
Other biotechs mulling a similar path face a deadline of sorts on deciding to use the workaround, as fourth quarter financials will soon become available. Registration statements would generally become outdated by mid-February and require fresher, audited financials, which would likely further delay IPOs.
While the question-and-answer document from the Nasdaq provides some clarity on what companies it would accept for listing, it discussed terms generally and will act on a case-by-case basis.
If a company has already cleared all SEC comments before the shutdown, the Nasdaq will list the proposed offering. If a company has outstanding comments but says it has fully resolved the issues, the exchange will consider a listing.
For companies in the earlier IPO stages, who have yet to receive SEC comments or first filed during the shutdown, the legal workaround appears much less viable. Exchange officials did state, however, they are open to discussions over “controls, standards and processes that could adequately protect investors while allowing capital raising activity to continue.”
In Gossamer’s case, it appears the company already worked through several rounds of comments with the SEC, as agency filings show multiple drafts of its registration statement dating back to October 2018.
If the shutdown ends and the SEC reverts back to normal before then, the biotech would re-evaluate the use of this legal workaround, the company stated in a Jan. 23 release. Gossamer would be the industry’s first IPO of 2019.
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Why once-promising cancer drugs fail


Nearly two decades after a class of once-promising cancer drugs called MMP inhibitors mysteriously failed in clinical trials, scientists think they may have an explanation for what went wrong.
The findings in C. elegans worms could lead to better ways to prevent the first steps of metastasis, the spread of the disease responsible for 90 percent of cancer deaths.
MMP inhibitors were aimed at blocking a group of enzymes long thought key to cancer’s spread. Called matrix metalloproteinases, the enzymes help dissolve the tough outer membrane that surrounds both tumors and healthy tissues, allowing cancer cells to escape from their original locations and set up shop in other organs.
Yet despite promising results in mice, MMP inhibitors didn’t help people with cancer live longer and some patients developed serious side effects.
The new findings, from a team led by biology professor David Sherwood at Duke University, suggest that invasive cells switch to brute force and build a battering ram when their dissolving enzymes aren’t available.
The study will appear online January 24 in the journal Developmental Cell.
To metastasize, a tumor cell must first penetrate a dense sheet-like mesh of proteins and other molecules called the basement membrane, which surrounds tissues like a Kevlar wrapper.
Sherwood and his team study a similar process in transparent 1-millimeter worms, which — unlike human tumors — allow researchers to watch invading cells in action.
Normal worm cells use their MMP enzymes to help cut through the matrix of proteins in the basement membrane like molecular scissors, the researchers say. But cells in “knockout” worms lacking the MMP enzymes instead build a large protrusion that pummels and smashes its way through with brute force, said research scientist Laura Kelley, who led the experiments.
Normally the invading cell pushes through a narrow hole, “kind of like the escape tunnel in ‘The Shawshank Redemption,'” Sherwood said. “But in knockout worms it’s more like the Kool-Aid Man when he busts through walls.”
The researchers also found that the protrusion is filled with stiff networks of actin filaments for a harder-hitting punch. To fuel the blows, the cell also moves mitochondria — the power plants of the cell — to the site of the ram.
The team also developed a screening technique that enabled them to identify and target a mitochondrial gene that invasive cells rely on in the absence of MMPs, and were able to prevent the cells from breaking through.
The researchers hope their work in worms will identify drug targets that could one day be tested in combination with MMP inhibitors to better treat metastasis in humans.
If researchers can develop drugs that inhibit both MMP enzymes and the battering rams, they may be able to more effectively block cell invasion and keep cancer from spreading.
This research was funded by the American Cancer Society (129351-PF-16-024-01-CSM), the Leukemia and Lymphoma Society (3601-11/388-0036), the National Cancer Institute (4R00CA154870-03), the National Institutes of Health (F32GM103148, NIGMS R35, MIRA GM118049, R21HD084290), Foundation Association pour la Recherche sur le Cancer and the PSL Research University (ANR-10-IDEX-0001-02 PSL).
Story Source:
Materials provided by Duke University. Note: Content may be edited for style and length.
Journal Reference:
  1. Laura Kelley, Qiuyi Chi, Rodrigo Cáceres, Eric Hastie, Adam Schindler, Yue Jiang, David Matus, Julie Plastino and David Sherwood. Adaptive F-actin Polymerization and Localized ATP Production Drive Basement Membrane Invasion in the Absence of MMPs. Developmental Cell, 2019 DOI: 10.1016/j.devcel.2018.12.018
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