Search This Blog

Saturday, November 3, 2018

Repeated CBD Doses Required for Effective Pain Relief


Repeated administration of cannabidiol (CBD) is needed to reduce neuropathic pain and related anxiety, new research suggests.
In a study designed to evaluate the dose, treatment duration, and mechanism of action of CBD, the drug modulated nociception, decreased anxiety-like behavior, and increased serotonin activity in a rodent model of neuropathic pain.
CBD also acted on some specific receptors but not others, a finding that paves the way for future therapeutics based on this active component of cannabis.
“These results are clinically relevant, as CBD is known to exhibit few side effects and supports the initiation of clinical trials testing the efficacy of CBD-based compounds for treating neuropathic pain and comorbid mood disorders,” the investigators write.
One-time acute treatment is likely insufficient.
“The most effective neuropathic pain relief occurs after 1 week of daily CBD treatment,” senior author Gabriella Gobbi, MD, PhD, professor of psychiatry, Neurobiological Psychiatry Unit, McGill University, Montreal, Canada, told Medscape Medical News.
Using in vivo electrophysiology, these experiments demonstrated that CBD decreases serotonin firing after an acute injection. However, after 1 week of treatment, the firing of serotonin increased through the desensitization of the 5-HT1A receptor.
This is the same mechanism observed for selective serotonin reuptake inhibitors, which “also require a few days or weeks before having a therapeutic effect — likely because some neuroplastic event occurs at the level of the receptors,” Gobbi said.
“Translating this to a clinical setting, these results suggest that the best treatment with cannabidiol will be a chronic treatment, but further clinical studies have to confirm this,” she added.
The findings were published online in Pain.

Growing Research Interest

Research interest in CBD, a noneuphoric and nonaddictive cannabis component, is growing. Investigators are assessing a wide range of potential indications, including treatment of chronic pain, nausea, psychosis, and anxiety, as well as epilepsy.
In addition, in June, the US Food and Drug Administration (FDA) approved a purified formulation of CBD (Epidiolex oral solution, GW Pharmaceuticals) to treat two rare forms of epilepsy.
The current study is not the only one to evaluate CBD for the treatment of neuropathic pain. Previous researchers assessed CBD alone or in combination with tetrahydrocannabinol for this indication.
However, few studies have explored the effect of CBD on 5-HT neurotransmission in the dorsal raphe nucleus (DRN), Gobbi and colleagues write. This region of the brain is important because it is involved in both mood disorders and pain, they note.
The investigators studied 229 adult male Wistar rats. They assessed the effects of both acute CBD therapy and repeated low-dose CBD on neuropathic pain modulation and responses.
Through a series of tests, they studied the firing activity of neurons, nerve desensitization, and reactions to mechanical allodynia. They also evaluated behavior using an open field test, a forced swim test, an elevated plus maze test, and a novelty-suppressed feeding test.
Electrophysiologic recordings demonstrated that neuropathic pain provoked a maladaptation of 5-HT neurotransmission. This action in turn caused a decrease in the firing activity of spontaneously active DRN 5-HT neurons.

Effective Doses

The investigators also sought clarity on an effective dose of CBD. CBD has been used therapeutically in doses ranging from 2.85 to 50 mg/kg/day, “meaning that its therapeutic dose is still unclear,” the researchers note.
For acute treatment, they administered cumulative injections of 0.05 to 0.25 mg/kg of CBD and 10 to 50 mg/kg of D-lysergic diethylamide acid (LSD). They also administered a single injection of the 5-HT1A antagonist WAY 100635, the AM 251, and/or the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine.
By pretreating with these antagonists and then administering CBD, the investigators demonstrated that the 5-HT1A and TRPV1 receptors are involved in the agent’s mechanism of action and ruled out involvement of the CB1 receptor.
Repeated treatment showed that the lowest IV CBD dose needed to cause a significant decrease in 5-HT neuronal activity was 0.10 mg/kg. The difference was significant compared with vehicle preinjection in Bonferroni post hoc analyses (n = 9; P < .05).
In addition, a 0.25-mg/kg dose of CBD “completely shut down neuronal activity” (n = 9 ; P < .001), the researchers report.
Using the spared nerve injury model of neuropathic pain, “we found that repeated CBD treatment was able to prevent mechanical allodynia and anxiety-like behavior in rats experiencing neuropathic pain, but through different mechanisms,” they write.
The investigators note that TRPV1 channels were required for the antiallodynic but not the anxiolytic effects of CBD. In contrast, 5-HT1A receptors were required for the anxiolytic and, to a lesser extent, the antiallodynic effects of CBD.
These receptors are essential because multiple studies have demonstrated “that the 5-HT1A receptor is crucial for the mechanism of anxiety and depression relief,” Gobbi said.

“Very Surprising” Results

Gobbi noted that in the past 15 years, investigators have conducted many preclinical studies with THC, CB1 agonists, and fatty acid amide hydrolase inhibitors or endocannabinoid enhancers. However, “it was very surprising to see that CBD has a mechanism of action that is different from its ‘cousin’ drugs.”
The preclinical findings of this research support future clinical trials, Gobbi added.
“These animal studies suggest the indication for CBD use in humans’ neuropathic pain and comorbid anxiety,” Gobbi said. “We have a better idea about the doses in humans, [because] the FDA has conversion tables to translate doses from animals to humans, and…we know more about the length of treatment.”
Could the findings have new implications, given recent government approvals for use of cannabis? “I hope so,” she answered.
“Canada has legalized recreational cannabis and made medicinal cannabis more accessible, but little is yet known about medical cannabis. A lot of patients are using mixtures of THC [and] CBD without knowing the appropriate indications, doses, side effects, and interactions with other drugs,” Gobbi noted.
“This research — I hope — will encourage more systematic medical cannabis research to help patients and doctors to make more evidence-based choices,” she said.

Caution Urged

Commenting on the findings for Medscape Medical News, Yasmin Hurd, PhD, professor of neuroscience, psychiatry, and pharmacologic sciences, Icahn School of Medicine at Mount Sinai, New York City, said this is an interesting study “that provides strong preclinical findings in support of the antinociception and antianxiety effects of CBD relevant to the condition of neuropathic pain.”
Hurd added that she applauds the investigators’ use of multiple approaches — behavioral, pharmacologic, and electrophysical measurement of cell firing — because this strengthened the overall findings. She also said the research strategy provided insights about the different biological mechanisms associated with CBD’s analgesic and anxiolytic properties.
“Clinical trials are of course still necessary, but the findings suggest that CBD may be potentially beneficial as a future treatment in reducing chronic pain and anxiety, which are often comorbid in neuropathic pain and related conditions,” she said.
Hurd, who was not affiliated with this study, has authored a review article on the potential role of marijuana as an alternative to opioids for the treatment of addiction.
When also asked by Medscape Medical News to comment on the study, Joshua Aviram, PhC, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel, was less enthusiastic.
“Although mechanistic observations on animal models are critical to the understanding of phytocannabinoids activity, human chronic pain is much more complicated than the mere nociception process,” Aviram said.
“Until these findings can be substantiated in high-quality controlled trials or even cohort studies on chronic pain patients, no responsible clinical implications can be drawn from these findings on CBD activity,” he added.
Aviram, principal investigator of a systematic review and meta-analysis on the efficacy of cannabis-based medicines for pain management, was not affiliated with the current study.
The study was supported by a matching grant from the Ministere de l’Economie Science et Innovation du Quebec and Aurora Cannabis Inc. Dr Gobbi, Dr Hurd, and Mr Aviram have disclosed no relevant financial relationships.
Pain. Published online August 27, 2018. Abstract
Posted by at No comments:

Could nanotechnology innovation cut blood clotting, infections from implants?


McMaster researchers develop surface coating that repels bacteria, viruses, and living cells.

Researchers at McMaster University have developed a nanotechnology surface coating that repels bacteria, viruses, and living cells, an innovation that could hold promise to reduce the risk of infection or blood clotting from implants, such as grafts, replacement heart valves, and artificial joints. While the engineered surface repels everything, it can be modified to permit beneficial exceptions, enabling implants to bond to the body, for example.
The research was reported in the October 24 issue of the journal, ACS Nano.
To understand the challenges related to making successful implants, researchers collaborated with Jeffrey Weitz, MD, professor of medicine, biochemistry and biomedical sciences at McMaster University, and executive director of the Thrombosis and Atherosclerosis Research Institute.

‘ENORMOUS’ IMPLICATIONS

The implications could be “enormous,” says Weitz. “We’ve made so many advances in these devices, but clotting on these devices is still a huge problem. One of the last frontiers is how to improve hemocompatibility—compatibility of the device with the blood in which it is sitting. The materials are getting better, but despite advances in material science, we still have a problem.”
Coating the surface of these device and making them slippery to prevent clotting is the first step, Weitz says. The next step is to “add something that then attracts the endothelial cells so that they get the same lining that normal blood vessels have.”
Weitz also sees opportunities to use the coating on central venous catheters, as well as the grafts he uses to treat peripheral artery disease. “It really does have the potential to save limbs in someone who has peripheral artery disease. This could be a huge advance.”
The next phase of research to develop clinical applications is underway. Weitz says it may be five years before a clinically viable solution is available.
“It was a huge achievement to have completely repellent surfaces, but to maximize the benefits of such surfaces, we needed to create a selective door that would allow beneficial elements to bond with those surfaces,” explained Tohid DIdar, PhD, assistant professor of McMaster’s Department of Mechanical Engineering and School of Biomedical Engineering, in a news release.
Didar is the senior author of the ACS Nano journal article, which indicated “…this straightforward and simple method creates biofunctional, nonsticky surfaces that can be used to optimize the performance of devices such as biomedical implants, extracorporeal circuits, and biosensors.”
Applied to a synthetic heart valve, the repellent coating could prevent blood cells from sticking and forming clots.
“A coating that repels blood cells could potentially eliminate the need for medicines such as warfarin that are used after implants to cut the risk of clots,” said co-author Sara M. Imani, a McMaster biomedical engineering doctoral student, in the news release.

REPELS AND ATTRACTS

A completely repellent coating, however, would also prevent the body from integrating the new valve into the tissue of the heart itself. By designing the surface to permit adhesion only with heart tissue cells, the researchers make it possible for the body to integrate the new valve naturally, avoiding the complications of rejection. The same would be true for other implants, they say, such as artificial joints and stents used to open blood vessels.
“The research adds significant utility to completely repellent surfaces that have existed since 2011,” according to the release. “Those surface coatings are useful for waterproofing phones and windshields, and repelling bacteria from food-preparation areas, for example, but have offered limited utility in medical applications where specific beneficial binding is required.”
The novel surfaces created through the latest research promote targeted binding of desired species, while simultaneously preventing nonspecific adhesion, according to the study.
Researchers speculate the new nanotechnology also may have additional medical applications. Outside the body, selectively designed repellent surfaces could make diagnostic tests much more accurate by allowing only the particular target of a test—a virus, bacterium or cancer cell, for example—to stick to the biosensor that is looking for it, a critical advantage given the challenges of testing in complex fluids, such as blood and urine.
Posted by at No comments:

Molina increases guidance despite declining net income


2018 has marked a positive turnaround for Molina Healthcare after leadership and financial instability in 2017.

KEY TAKEAWAYS

After a topsy-turvy 2017, the insurer has performed more consistently in 2018, raising its year-end outlook.
This comes despite decreases to net income and earnings per share in Q3.
Nonetheless, CEO Joe Zubretsky is impressed with Molina’s “continued performance.”
Net income and premium revenues declined for Molina Healthcare in Q3, though the Long Beach-based insurer raised its financial guidance for the end of the year, according to its Q3 earnings report released Wednesday afternoon.
Molina’s net income totalled $197 million, down $5 million from Q2, while premium revenues dipped 4% to $177 million. Molina attributes this drop to risk adjustment premiums from last year that were not recognized in Q2 as well as $57 million in retroactive Medicaid expansion risk corridor payments in California.
The quarterly earnings mark a shift for Molina, which saw significant financial upheaval following a major reorganization effort in 2017.

C-SUITE PERSPECTIVE:

“We are very pleased with the continued improvement in the performance of our business,” Joe Zubretsky, CEO of Molina Healthcare, said in a statement. “Our financial results reflect the significant progress we are making in executing our margin recovery and sustainability plan.”
In response to its Q3 earnings report, Molina has improved its end-of-year financial guidance by $1.65 per diluted share to a range of $8.80 to $9.

ADDITIONAL MOLINA Q3 EARNINGS REPORT HIGHLIGHTS:

  • In Q3 2017, Molina reported a $97 million loss in net income, further emphasizing the company’s turnaround.
  • The insurer’s net income margin totalled 4.2% for Q3, including 3.6% for the year.
  • Molina also repaid $140 million in outstanding debt in Q3, bringing their half-year total to $697 million.
For complete financial information, review Molina’s filing with the Securities and Exchange Commission.
Posted by at No comments:

Athenahealth pushes back Q3 earnings amid Veritas-Elliott talks

ogy servicer unexpectedly delayed releasing its Q3 earnings report Thursday afternoon as reports surface about multiple bidders seeking to purchase the company.

KEY TAKEAWAYS

athenahealth’s rescheduled earnings report will be released November 9 after the markets close.
The decision comes amid talks of a joint bid between Veritas Capital and Elliott Management to purchase the company.
The health technology servicer’s stock was trading down by more than 1.7% early Friday morning.
Watertown, Massachusetts-based aethnahealth pushed back releasing its Q3 earnings report and conference call as the talks continue with Veritas Capital and Elliott Management Corp. about a potential acquisition of the company.
The new announced time for earnings will be Friday, November 9 after the markets close, with an investor conference call scheduled for Monday, November 12 at 5 p.m. EST., according to a company press release issued Thursday afternoon.
While athenahealth did not elaborate on the weeklong delay in the announcement, there have been multiple press reports recently suggesting that the company is close to being acquired by Veritas Capital and Elliott Management in a joint bid.
Bloomberg reported on Wednesday that Veritas and Elliott were engaged in ongoing negotiations to purchase the embattled health technology servicer. The basic framework of the deal would see Elliott increase its investment stake beyond the current 9%, according to the report.
A representative for athenahealth did not immediately respond to a request for comment.
In early October, The New York Post reported that athenahealth was reaching out to investors that expressed prior interest in purchasing the company.
However, these potential suitors were offering far lower bids than billionaire hedge fund manager Paul Singer, owner of Elliott Management Corp., had offered in May. Singer proposed purchasing athenahealth at $160 per share, per due diligence.
After seeing the company’s financial records though, Singer backed off his bid, and during the next month Elliott encouraged then-CEO Jonathan Bush to resign after reports surfaced of domestic violence and misconduct.

Despite an eventful run during Q2, athenahealth managed to post a solid quarterly earnings report in late July. However, upon news of the delayed Q3 earnings report, athenahealth’s stock was down more than 1.72% during early trading Friday morning.
Posted by at No comments:

LifePoint board OK with $120 million pay plan despite shareholder rejection


LifePoint Health’s board of directors is plowing ahead with a $120 million golden parachute plan for four top executives ahead of the company’s sale, despite overwhelming opposition from shareholders.
The board itself, which will disband when the deal goes through, is getting more than $11.3 million, not counting the company’s chairman and CEO’s take, as part of the sale.
The payouts are raising eyebrows in the investment community given they total more than the company’s 2017 net income. Analysts, attorneys and others who follow the industry say the unusually high level of backlash the investor-owned hospital company’s golden parachutes proposal received—including rejection from owners of 83% of voting shares and opposition from two leading proxy advisory firms—could come back to haunt LifePoint directors who serve on other boards and should serve as a cautionary tale for other companies establishing such severance packages ahead of acquisition deals.
“It’s a signal to the market that this type of approach is a problem and investors are not happy with it,” said Julian Hamud, director of executive compensation research with proxy advisory firm Glass Lewis. “But as it relates to LifePoint specifically, that’s not necessarily going to do a lot.”
Federal securities law required Brentwood, Tenn.-based LifePoint, which expects to close on its sale to affiliates of the private equity firm Apollo Global Management by year-end, to hold a nonbinding shareholder vote last week on the golden parachutes plan. The results were never going to carry any weight, however: The cash severance and other payout provisions were already in executives’ contracts. The stock awards outlined in the plan will be paid upon the Apollo deal’s closing.


Companies not entering buyouts would face significant pressure to change their pay packages under such conditions, but in this case, it’s just the reputational risk for directors. David Teigman, a partner with Cadwalader, Wickersham & Taft in New York and the head of its executive compensation practice, questioned whether the situation could impact directors’ abilities to serve as directors at other companies.
Several of LifePoint’s directors already serve on other boards, and Glass Lewis’ Hamud said this case raises the question of whether LifePoint shareholders who hold stock in those companies might take their concerns there.
“I think that the question of accountability is a very good one when it relates to these merger situations,” he said. “It also depends on how far investors are willing to track individuals.”
LifePoint director Kermit Crawford, for example, is chief operating officer of Rite Aid Corp. That company’s shareholders last week rejected an executive pay program that some dubbed “pay for failure” because it follows Rite Aid’s failed deal with Albertsons.
The International Brotherhood of Teamsters urged shareholders to vote against the Rite Aid proposal. Michael Pryce-Jones, the Teamsters’ senior governance analyst, said his organization evaluates proposals on a case-by-case basis, but generally will oppose situations where executive pay is going up while shareholder returns dwindle. The Teamsters last year urged shareholders to rejectTenet Healthcare’s compensation plan, arguing then-CEO Trevor Fetter had performed poorly in 2016. The Teamsters do not hold LifePoint stock.
LifePoint director and chair of the board’s compensation committee John Maupin Jr., serves as a director of Encompass Health, a post-acute healthcare management company. LifePoint Director Dr. Reed Tuckson, a former UnitedHealth Group executive, serves on the board of the American Telemedicine Association, CTI BioPharma Corp. and the Alliance for Health Reform.
LifePoint’s seven directors, excluding CEO Bill Carpenter, will receive a combined $11.3 million for shares they own once the Apollo deal closes based on their roughly 173,000 shares of common stock. Carpenter will receive $140 million based on his 2.2 million shares of common LifePoint stock. Directors also owned varying amounts of restricted stock that may translate into cash after the deal is closed.
And that’s on top of the director’s regular salaries. Last year, LifePoint’s directors took home annual pay of between $140,000 and $215,000.
Calls to directors were referred back to LifePoint, which declined to comment on the parachute plan beyond what was in the proxy statement.

WHAT’S UNDER THOSE PARACHUTES, ANYWAY? Under LifePoint Health’s golden parachutes plan, severance payments to four top executives would be triggered if:
• Their employment is terminated without cause within two years after the closing of the Apollo deal
• They’re not offered positions “substantially equivalent” to their roles before the deal, or
• They leave voluntarily because they don’t feel their positions are “substantially equivalent.”
The payments range from $2.7 million to $8.8 million. The lump sums are equal to 300% of the executives’ normal annual compensation.
If those conditions are met, the executives would also receive an additional cash bonus, continued medical, life, disability and other benefits for a year and attorney fees and costs incurred making claims for payment.
The plan applies to LifePoint CEO Bill Carpenter, who plans to step down once the deal is complete, Chief Operating Officer David Dill, Chief Financial Officer Michael Coggin and Chief Administrative Officer John Bumpus.
Once the sale closes, those four executives will receive a combined $67.5 million in stock awards—between $5.7 million and $41.3 million each. That could be enough to trigger a federal excise tax, said David Teigman, a partner with Cadwalader, Wickersham & Taft in New York and the head of its executive compensation practice.
Some companies pay departing executives excise tax gross-up provisions, which are designed to offset the taxes. In this case, LifePoint’s golden parachutes plan includes $33.5 million in excise tax gross-ups, or between $3 million for Bumpus and up to $19.5 million for Carpenter.
All told, the plan outlined $69.7 million in payments to Carpenter, $25 million to Dill, who is set to replace Carpenter as CEO, $13.4 million to Coggin and $11.5 million to Bumpus.
Despite the golden parachutes provisions already being in executives’ contracts, Hamud said employment matters are largely negotiable between directors and executives, unless they’re structured in a way that doesn’t permit changes. One example was when Valeant Pharmaceuticals’ CEO agreed to forgo a massive stock award after shareholders expressed opposition.
“So yes, it was an entitlement,” he said. “It was ink on page, but that shareholder pressure moved the board to make steps that the CEO ultimately agreed to.”
But Teigman said the opposition is unlikely to change anything at LifePoint. “They’ve already entered into a merger agreement that calls for acceleration of the equity to be cashed out and they also have arrangements with these executives to pay out these amounts if they’re terminated, so I would not expect them to follow this vote,” he said.
To that end, LifePoint spokeswoman Michelle Augusty wrote in an email that compensation under LifePoint’s existing compensation programs, as contemplated by the merger agreement, will be paid in accordance with its terms outlined in a proxy statement. She declined to comment further.
In the future, companies can mitigate the risk of similar events by upping their shareholder engagement and taking a hard look at their compensation packages to predict whether they would run into proxy adviser opposition, Teigman said.
The Dodd-Frank Act of 2010 requires companies to bring executive compensation proposals before their shareholders annually, a process called “say on pay.” Shareholders don’t have an official say over compensation, although at least 25% opposition should prompt companies to retool them, Pryce-Jones said. The same standard applies in theory to severance pay, although companies about to merge or be sold are less likely to respond to shareholder opposition, he said.
After the Teamsters ran a successful bid against McKesson Corp.’s executive pay plan in 2017, the company cut its CEO’s pay by about 10%. The pay package received about 27% support from shareholders.
Both of the two most influential proxy advisory firms, Institutional Shareholder Services and Glass Lewis, urged their clients to vote against LifePoint’s golden parachutes proposal, a level of unified opposition that’s “very rare,” said Jason Plagman, an analyst with Jefferies & Co.
ISS wrote in a report that it opposed the plan because the awards were set at maximum levels without compelling rationale. ISS also opposed the plan’s use of excise tax gross-ups, which it described as “a poor practice.” ISS declined to comment for this article.
Glass Lewis’ main opposition was the high value of the golden parachute packages relative to the total equity premium the Apollo deal would generate. Glass Lewis determined 18% of the share value gained from the sale of the company could be reflected in the value of the parachute payments, Hamud said. With companies of LifePoint’s size, Glass Lewis expects that to be around 10%, he said.
Brian Tanquilut, an analyst with Jefferies, said he doesn’t believe this will change how hospital companies formulate their future compensation packages, most of which include change-in-control provisions like LifePoint’s. He noted LifePoint’s deal with Apollo includes a payout for shareholders: $65 per share in cash.
“It’s an alignment of incentives, in a way,” Tanquilut said.
Posted by at No comments:

Cooling ‘brains on fire’ to treat Parkinson’s


A promising new therapy to stop Parkinson’s disease in its tracks has been developed at The University of Queensland.
UQ Faculty of Medicine researcher Associate Professor Trent Woodruff said the team found that a small molecule, MCC950, stopped the development of Parkinson’s in several animal models.
“We have used this discovery to develop improved drug candidates and hope to carry out human clinical trials in 2020,” Dr Woodruff said.
“Parkinson’s disease is the second-most common neurodegenerative disease worldwide, with 10 million sufferers, whose control of body movements is affected.
“The disease is characterised by the loss of brain cells that produce dopamine, which is a chemical that co-ordinates motor control, and is accompanied by chronic inflammation in the brain.
“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood.
“MCC950, given orally once a day, blocked NLRP3 activation in the brain and prevented the loss of brain cells, resulting in markedly improved motor function.”
There are no medications on the market that prevent brain cell loss in Parkinson’s patients, with current therapies focusing on managing symptoms rather than halting the disease.
UQ Institute for Molecular Bioscience researcher Professor Matt Cooper said drug companies had traditionally tried to treat neurodegenerative disorders by blocking neurotoxic proteins that build up in the brain and cause disease.
“We have taken an alternative approach by focusing on immune cells in the brain called microglia that can clear these toxic proteins,” he said.
“With diseases of ageing such as Parkinson’s, our immune system can become over-activated, with microglia causing inflammation and damage to the brain.
“MCC950 effectively ‘cooled the brains on fire’, turning down microglial inflammatory activity, and allowing neurons to function normally.”
The study is published in Science Translational Medicine, and was made possible by generous support from The Michael J. Fox Foundation for Parkinson’s Research and Shake it Up Australia Foundation, which fund innovative research into therapies for Parkinson’s disease.
“We are extremely grateful to our funders who have supported multiple research projects on this target at UQ, and to their donors who support medical research for those living with Parkinson’s,” Dr Woodruff said.
The study was undertaken at the School of Biomedical Sciences and involved UQCCR Group Leader in Clinical Neuroscience Dr Richard Gordon, an Advance Queensland Research Fellow, and PhD student Eduardo Albornoz.
“The findings provide exciting new insight into how the spread of toxic proteins occurs in Parkinson’s disease and highlights the important role of the immune system in this process,” Dr Gordon said.
“With continued funding support, we are exploring new treatment strategies including repurposing drugs to target mechanisms by which the immune system and the inflammasome contribute to disease progression.”
Story Source:
Materials provided by University of Queensland. Note: Content may be edited for style and length.
Journal Reference:
  1. Richard Gordon, Eduardo A. Albornoz, Daniel C. Christie, Monica R. Langley, Vinod Kumar, Susanna Mantovani, Avril A. B. Robertson, Mark S. Butler, Dominic B. Rowe, Luke A. O’Neill, Anumantha G. Kanthasamy, Kate Schroder, Matthew A. Cooper, Trent M. Woodruff. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Science Translational Medicine, 2018; 10 (465): eaah4066 DOI: 10.1126/scitranslmed.aah4066
Posted by at No comments:

Pre-Existing Immunity to CRISPR Found in 96% of People in Study


The immune systems of a large majority of people could already be primed to attack and possibly even disable a key component of CRISPR-Cas9 gene editing therapeutics (which are quickly moving towards their first human tests), suggests new research published today.
If this finding sounds familiar, it’s because another paper, posted in January before being peer reviewed, reached similar conclusions, plunging stock prices of CRISPR companies—CRISPR Therapeutics (NASDAQ CRSP), Editas Medicine (NASDAQ EDIT) and Intellia Therapeutics (NASDAQ NTLA).
Today’s paper, published in the peer-reviewed journal Nature Medicine, suggests those results from January weren’t a fluke. In the latest research, a team of scientists in Germany exposed blood samples from 48 healthy volunteers to Cas9 (a DNA-cutting enzyme) derived from a bacterium called Streptococcus pyogenes. (Cas9 from S. pyogenes is one of the most common DNA-cutting enzymes used in CRISPR R&D, if not the most commonly used.)
The researchers found that 96 percent of the people in the study had T-cell based immunity against Cas9, and 85% had antibodies against it. Those are higher rates than what the other research team, led by Matthew Porteus of the Stanford School of Medicine, showed in January. The Porteus group found that 65% of donors had antibodies against Cas9 from S. pyogenes, but couldn’t detect T cell activity against that enzyme. Previous research from other teams has shown pre-existing immunity in lab animals.
Michael Schmueck-Henneresse of Charité University Medicine Berlin, who led today’s study, said that he was initially surprised by the 96% finding. “But it made sense because the Streptococcus pyogenes bacterium is one of the most common causes for bacterial infections in humans and we have all been through multiple infections and potentially even been colonized by it,” he wrote in an email.
Porteus said in an email the latest results show that issue of immunity to CRISPR-Cas9 “remains one that needs to be closely considered.”
What does this mean for CRISPR-based therapeutics, which could enter human tests as early as next year? “At this point, we cannot predict what will happen [in humans],” Schmueck-Henneresse said. It will depend on a variety of factors, such as how the CRISPR-Cas9 system is packaged and delivered throughout the body and what tissue is being targeting, he added.
Intellia Therapeutics says it has been on the lookout for T-cell based immunity against its CRISPR system. The company is developing CRISPR as a medicine that’s delivered to the body to treat various genetic diseases. (Its other programs use CRISPR to modify cells outside of the body, where this pre-existing immunity should be less of an issue.) For the in vivo programs, Intellia is using lipid nanoparticles (LNPs) to deliver CRISPR to the liver. Jenn Smoter, Intellia spokesperson, said Intellia researchers have tested their LNPs in lab animals. “We have seen no evidence of T cell-mediated cytotoxicity to the cells expressing Cas9.”
Schmueck-Henneresse urges caution going into clinical trials. He says CRISPR drug developers should minimize the amount of time Cas9 is active in cells, and they could consider giving the first patients immune-suppressing drugs.
Other researchers have also raised a red flag around another CRISPR effect: unintended edits in off-target spots along the genome. But pre-existing immunity to Cas9 is more of a worry than off-target edits, wrote Gaetan Burgio, a genome-editing expert at Australian National University, on Twitter in April, in reaction to a not-yet-peer-reviewed version of today’s study.
But in a tweet in response to the latest version of the paper, Burgio wrote that there are ways to circumvent the immunity issue.
Gaetan Burgio@GaetanBurgio
Published now in @NatureMedicine on  & Immunity to SpCas9. 6 months has past since the preprint was online & it is a long time in the CRISPR field. Since then additional work showed how to circumvented this by modifying Cas9 protein or using Cas9 orthologs. So No panic !
Gaetan Burgio@GaetanBurgio
Wow, just wow ! ‘For in vivo application of #CRISPR,
immunosuppressive treatment must be considered’ -> to control pre-existing immune response against Cas9 https://www.biorxiv.org/content/early/2018/04/04/295139 …
View image on Twitter
5:45 AM – Oct 30, 2018
Another possible way around the immunity issue is to use other kinds of DNA-cutting enzymes. That may not be a straightforward solution, Schmueck-Henneresse says, because other Cas enzymes come from bacteria that humans are often exposed to. Indeed, his team tested other enzymes such as Cpf1 and found similar immune reactions. He suggests pursuing Cas9 from bacteria that are not known to infect humans.
Still Schmueck-Henneresse says there’s no reason to panic. “Our results are a warning, but immunogenicity has been a problem in the field of gene therapy for a long time,” he says.
Posted by at No comments:
Subscribe to: Posts (Atom)