Potential way to grow new teeth for patients

A group of histologists and dentists from School of Biomedicine, Far Eastern Federal University (FEFU), teamed up with Russian and Japanese colleagues and found cells that are probably responsible for the formation of human dental tissue. Researchers propose to apply the study outcome within the development of bioengineering techniques in dentistry aimed at growing new dental tissue for patients. A related article is published in the International Journal of Applied and Fundamental Research.

FEFU scientists used human prenatal tissues to study the early stage of development of the embryonic oral cavity during the period when the teeth were set up – from the 5th to the 6th week. They have recognized several types of cells that are involved in the formation of one of the teeth rudiments — the enamel (dental) organ. Among them, chromophobe cells with elongated spindle-shaped form have been identified which are also responsible for the development of human teeth in the first weeks of embryo formation. The data obtained can provide a fundamental basis for the development of bioengineering therapies in dentistry and gastroenterology.

‘Numerous attempts to grow teeth from only the stem cells involved in the development of enamel, dentin and pulp, i.e. ameloblasts and odontoblasts, were not successful: there was no enamel on the samples, teeth were covered only by defective dentin. The absence of an easily accessible source of cells for growing dental tissue seriously restricts the development of a bioengineering approach to dental treatment. To develop technologies of tissue engineering and regenerative medicine — promising methods of treatment in dentistry — the cells identified by us may become the clue to the new level of quality dental treatment. Natural implants that are completely identical to human teeth will no doubt be better than titanium ones, and their lifespan can be longer than that of artificial ones, which are guaranteed for 10-15 years. Although for a successful experiment, we still have a lack of knowledge about intercellular signaling interactions during the teeth development.’ said Ivan Reva, Senior Researcher of the Laboratory for Cell and Molecular Neurobiology, School of Biomedicine, FEFU.

The scientist noted that large chromophobe cells reside not only the place where the teeth of the embryo form, but also exist at the border where the multilayers squamous epithelium of the oral cavity passes into the cylindrical epithelium of the developing digestive tube. This means that the new bio-engineering approach is relevant not only for growing new dental tissue but also for growing organs for subsequent transplantation and likely will be applied in gastroenterology.

The development of new biological approaches for the teeth reconstruction with stem cells is one of the most pressing tasks in dentistry for the upcoming years. There are still a lot of questions challenging the researchers. For example, scientists have yet to figure out how in the earliest stages of human embryo development, from the seemingly homogeneous, and in fact, multilayered ectoderm, which is located in the forming oral cavity, different types and forms of teeth develop. However, it is already clear that more kinds of cells are engaged in the earliest stages of human teeth formation than it was previously supposed. Thanks to the research of FEFU scientists in cooperation with their colleagues from Russia and Japan, it also became clear that the crown of the tooth and its root have different mechanisms of formation.

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This work was supported by the FEFU Scientific Foundation, within the framework of the state task 17.5740 / 2017 / 6.7.

https://www.eurekalert.org/pub_releases/2019-06/fefu-fsl062719.php

Society pays heavy price for failure to diagnose and treat conduct disorder

Much greater awareness, improved diagnosis and enhanced treatment are all required in order to reduce the burden on society of the severe behavioural condition conduct disorder, according to a new expert review led by the University of Bath (UK).

Conduct Disorder (CD), which is a common and highly impairing psychiatric disorder, usually emerges in childhood or adolescence and is characterized by severe antisocial and aggressive behaviour, including physical aggression, theft, property damage and violation of others’ rights.

Its prevalence is estimated at around 3% in school-aged children and it is a leading cause of referral to child and adolescent mental health services. Yet paradoxically it is one of the least widely recognised or studied psychiatric disorders, and funding for research into CD lags far behind many other childhood disorders.

What the evidence shows is that CD is associated with an exceptionally high individual, societal and economic burden. The health and personal burden of CD is seven times greater than that of attention-deficit/hyperactivity disorder (ADHD), a much more widely known disorder. Whilst it is likely that children diagnosed with ADHD may also show signs of CD, very few will be diagnosed or receive treatment for the CD. CD is also associated with a greater health burden than autism.

This failure to tackle and treat CD in children and adolescents led the researchers to write the new Nature Reviews paper which calls for a greater awareness of the condition, and more funding to improve our understanding and ability to treat the disorder.

The review – a comprehensive overview of all aspects of CD, its diagnosis, clinical management and long-term impact – highlights the negative consequences and adult outcomes that can occur if it is not correctly diagnosed or treated.

In particular it reveals the high physical and mental health burden on patients and their families. In children, CD is associated with a higher risk of developing ADHD, oppositional defiant disorder and developmental language disorders; while for teenagers, comorbidities can include depression, anxiety, alcohol and substance abuse. Up to 50% of individuals with CD develop antisocial or borderline personality disorder in adulthood, along with more serious criminal behaviour and gang involvement.

It also finds that young people with CD are more likely to have children earlier, with more unplanned pregnancies, to become dependent on benefits, homeless or even to attempt suicide. Such behaviours have a huge detrimental effect on an individual and their families. In addition, those with CD display parenting problems which often mean that their own children are at higher risk for developing CD.

However, the researchers suggest that with the correct diagnosis, management for the condition is possible with the support of Child and Adolescent Mental Health Services (CAMHS). Their study highlights the value of both training parents in better supporting children with CD, and skills training for children and adolescents with the condition to help them improve their social and problem-solving skills and their ability to regulate emotions. Combined, the authors suggest, these approaches can have profound impacts on a patient’s well-being and longer-term life chances.

Lead author Dr Graeme Fairchild from Bath’s Department of Psychology hopes the study can act as a catalyst to improve the diagnosis and treatment of children with CD, and to highlight the societal impact of the condition which he suggests requires more government funding and charity involvement.

He explains: “Despite the fact that it is associated with a very high personal, familial, and societal burden, Conduct Disorder is under-recognised and frequently goes undiagnosed and untreated. The government have committed to increasing the funding for the treatment of child and adolescent mental health problems. They should take this opportunity to improve the diagnosis and treatment of children and teenagers with Conduct Disorder by investing in training in evidence-based treatments for this condition and ensuring that the families in question can access Child and Adolescent Mental Health Services. Research in other European countries and the United States has shown that this kind of investment will pay for itself over time.”

Recent other publications from Dr Fairchild have identified brain wiring differences in children with conduct disorder as well as altered brain activity in antisocial girls.

https://www.eurekalert.org/pub_releases/2019-06/uob-sph062719.php

Mini ‘magic’ MRI scanner could diagnose knee injuries more accurately

IMAGE: THIS IS A PROTOTYPE ‘MINI’ MRI SCANNER, DEVELOPED BY IMPERIAL COLLEGE LONDON, THAT COULD BE USED FOR DIAGNOSING KNEE INJURIESview more 

CREDIT: IMPERIAL COLLEGE LONDON / JOURNAL OF MAGNETIC RESONANCE IN MEDICINE

Researchers at Imperial College London have developed a prototype mini MRI scanner that fits around a patient’s leg.

The team say the device – which uses so-called ‘magic angle’ effect – could potentially help diagnose knee injuries more quickly, and more accurately.

In a proof-of-concept study using animal knees, the results suggest the technology could be used to show all the structures of the knee.

The scientists say the device (which looks like a large metal ring through which a patient places their leg) could help diagnose conditions such as anterior cruciate ligament injuries – particularly common among footballers.

Furthermore, the small size of the device could enable it to be used in local clinics and even GP surgeries, potentially reducing NHS waiting times for MRI scans.

The research was funded by the National Institute for Health Research.

Currently, key components of the knee joints such as ligaments and tendons are difficult to see in detail in the MRI scans, explains Dr Karyn Chappell, a researcher and radiographer from Imperial’s MSK Lab: “Knee injuries affect millions of people – and MRI scans are crucial to diagnosing the problem, leading to quick and effective treatment. However we currently face two problems: connective tissue in the knee is unclear on MRI scans, and people are waiting a long time for a scan.”

Dr Chappell added: “This can cause particular problems for women, as they are at greater risk of anterior cruciate ligament injuries. The reasons for this are unclear, but it could be linked to hormones such as oestrogen making ligaments more elastic, leading to more joint injuries.”

Knee injuries commonly affect one of three areas: the tendons (which attach muscle to bone), the meniscus (a cushioning pad of cartilage that prevents the bones of the joints rubbing together), or the ligaments (tough bands of connective tissue that hold bones in a joint together).

Following knee injury a doctor may refer a patient for a MRI scan to help establish which part of the joint is injured. MRI scans use a combination of radio waves and strong magnets to ‘flip’ water molecules in the body. The water molecules send out a signal, which creates an image.

However, tendons, ligaments and meniscus are not usually visible with MRI, due to the way water molecules are arranged in these structures, explains Dr Karyn Chappell.

“These structures are normally black on an MRI scan – they simply don’t produce much signal that can be detected by the machine to create the image. This is because they are made mostly of the protein collagen, arranged as fibres. The collagen fibres hold water molecules in a tight configuration, and it is in fact water that is detected by the MRI. If you do see a signal it suggests there is more fluid in the area – which suggests damage, but it is very difficult for medical staff to conclusively say if there is injury.”

To overcome this problem, Dr Chappell harnessed the power of a phenomenon called the ‘magic angle’: “The brightness of these tissues such as tendons and ligaments in MRI images strongly depends on the angle between the collagen fibres and the magnetic field of the scanner. If this angle is 55 degrees the image can be very bright, but for other angles it is usually very dark.”

The team explain the magic angle is achieved in their scanner because they are able to easily change the orientation of the magnetic field. While the patient sits comfortably in a chair, the specially designed magnet (which uses motors and sensors similar to those found in robots in car factories) can rotate around the leg and the orientate magnetic field in multiple directions.

This is not possible in current hospital MRI scanners, which are also much more expensive than the prototype scanner.

“Previously the magic angle phenomenon was thought of as a problem, as it could mean medical staff mistakenly thinking the knee is injured. However, I realised that if we took a number of scans around the knee, we could use the signal produced by the magic angle effect to build a clear picture of the knee structures,” explained Dr Chappell.

“Specifically, we can combine images obtained at different magnet angles and not only increase the brightness, but also see how the collagen fibres are arranged. This enables us to establish the pattern of collagen fibres in the knee structures, which is crucial information ahead of treatments such as repairing a torn meniscus,” added Dr Chappell.

“At the moment, it’s very difficult to see which direction the collagen fibres run in a meniscus. This is important because sewing across the fibres will effectively repair a tear in the meniscus. However if the stitch is in the same direction as the fibres, the repair may fail.”

In a new study, published in the journal Magnetic Resonance in Medicine, the multi-disciplinary team scanned the knee joints of six goats and ten dogs in a conventional MRI scanner.

All of the dog legs were donated by the Royal Veterinary College, having been donated for research by dog owners following the death of their pet.

Dogs suffer from knee injuries and arthritis similar to humans, making them a good subject for the study.

The results showed that using the magic angle can accurately detect ligament and tendon damage.

The team say now they know magic angle scanning can be used to visualise the knee, combining this with the new prototype mini scanner could enable knees to be accurately scanned with this technology – and hope to progress to human trials of the ‘mini’ scanner within a year.

Dr Chappell explained: “Although this is an early-stage proof-of-concept study, it shows the technology could potentially be used to accurately detect knee injury. We now hope to enter human trials – and explore if this technology could be used for other joints such as ankles, wrists and elbows.”

https://www.eurekalert.org/pub_releases/2019-06/icl-mm062819.php

Karyopharm awaits a verdict on selinexor

A delayed decision on Karyopharm’s selinexor is the pick of the bunch for July.

On the US approvals front a quiet June is about to give way to an even quieter July. But the fact that 2019 has, so far, been a relatively slow year for the FDA will not bother Karyopharm if it can get the nod for its lead candidate, selinexor.

The project is due a decision in multiple myeloma by July 6, a three-month delay to its original PDUFA date, and approval is far from assured. Assets from Merck & Co and Shield Therapeutics are also in line for consideration, while Celgene’s Otezla could get a thumbs-up in a new indication, Behçet’s disease, as Bristol-Myers Squibb looks for a buyer for the product.

The FTC said this week that Bristol would have to sell the psoriasis drug for its purchase of Celgene to go through; investors reacted by knocking nearly $6bn off Bristol’s market cap.

Approval in Behçet’s is unlikely to make much difference to Bristol’s negotiations: the inflammatory condition is rare in the US and Europe. Celgene previously said it would also seek a supplemental approval for Otezla in moderate to severe scalp psoriasis in the second quarter.

Take two for selinexor

Meanwhile, Karyopharm’s investors face a nervous wait over selinexor, which is awaiting a decision in relapsed/refractory multiple myeloma patients who have received at least three prior therapies. The company’s share price plunged in February after an FDA advisory panel recommended delaying approval until readout of the Boston trial in earlier-line patients.

The subsequent delay gave investors hope that accelerated approval could still be within reach, with analysts speculating that the company had submitted some of the Boston data to the agency early (Karyopharm’s selinexor delay could speed approval, March 15, 2019).

There are concerns about toxicity with selinexor, but the very sick population that Karyopharm is initially targeting could work in the company’s favour. Still, even if it is approved it might remain a last-ditch option, and moving into earlier lines of therapy could be another story. In February, EvaluatePharma sellside consensus put 2024 selinexor sales at $1.2bn; expectations have now dropped to $370m.

NOTABLE FIRST-TIME US APPROVAL DECISIONS DUE IN JULY
Project	Company	PDUFA date	Product NPV ($m)
Selinexor	Karyopharm	Jul 6	1,646
MK-7655A	Merck & Co	Jul 16	–
Feraccru	Shield Therapeutics	Jul 27	96
Source: EvaluatePharma.

Merck & Co is set to hear by mid-July on its latest antibacterial, a combination of relebactam, imipenem and cilastatin known as MK-7655A. The project is due a verdict in complicated urinary tract and intra-abdominal infections caused by certain Gram-negative bacteria in adults with limited or no alternative therapies.

Merck recently bagged approval for Zerbaxa, another antibacterial combination product, in the new use of pneumonia. Although there is a big need for new antibiotics, the market for such products is far from lucrative.

Meanwhile, a positive decision on the oral iron supplement Ferracru would give its originator, Shield Therapeutics, a big boost. The product is already available in Europe for the treatment of iron deficiency in patients with or without anaemia.

Finncap analysts expect Ferracru to get the US nod for iron deficiency anaemia, but noted that a general iron deficiency label would double the addressable market.

Shield’s future had looked dim after the failure of the Aegis-CKD trial in early 2018, but the UK company later carried out a new analysis, with better results. Earlier this year, the Aegis-H2H trial found that Ferracru was non-inferior to injectable iron. Shield will have to hope that this data package will be enough to convince the FDA.

Another project that could be due a nod is Samsung Bioepsis’s Humira biosimilar Imraldi, which was accepted for review by the FDA in September. Three other Humira biosimilars have US approval – Amgen’s Amjevita, Novartis’s Hyrimoz and Boehringer’s Cyltezo – although Humira’s maker, Abbvie, has agreements with most of their manufacturers to keep them off the market until 2023.

SUPPLEMENTARY AND OTHER NOTABLE APPROVAL DECISIONS DUE IN JULY
Product	Company	Event type	Date
Otezla	Celgene	sNDA for Behçet’s disease	Jul 21
Imraldi	Samsung Bioepis	Humira biosimilar; FDA accepted filing in Sep 2018	Possibly July
Source: EvaluatePharma.

https://www.evaluate.com/vantage/articles/events/upcoming-events/go-or-no-go-karyopharm-awaits-verdict-selinexor

Pivotal data readouts for Ardelyx and Rhythm will set the tone for next year

Both Ardelyx and Rhythm Pharmaceuticals are looking for phase III clinical wins to kick off filing discussions for pipeline leads.

Welcome to your weekly digest of approaching regulatory and clinical readouts.The next six months are going to be very busy for Ardelyx, which expects a raft of data with its lead project, tenapanor, in a number of indications.

First up is the phase III Amplify trial, looking at tenapanor as an adjunctive therapy to phosphate binders for patients with end-stage renal disease. The multipurpose asset is also looking to land its first approval, with a PDUFA decision in irritable bowel syndrome with constipation (IBS-C) due by September 12.

Tenapanor, a small molecule, targets the NHE3 transporter in the gut, resulting in the excretion of excess phosphate. While not in itself a treatment for renal disease it could reduce the pill burden of patients using phosphate binders, and therefore increase compliance.

The primary endpoint of the 214-patient Amplify study is change in serum phosphate levels after four weeks with tenapanor versus placebo. The project is also being tested as monotherapy in the phase III Phreedom study, which is due to read out in the fourth quarter. If it is successful in both trials it could become the only phosphate-lowering drug approved as a mono and adjunctive therapy.

In terms of IBS-C, tenapanor is designed to act directly in the gut to reduce absorption of sodium; this increases fluid in the gut, loosening stool and alleviating constipation. However, the project has had several setbacks in this setting, leaving it significantly behind the industry leader, Allergan’s Linzess.

TOP IBS-C PRODUCTS BY 2024
		Annual indication sales ($m)
Product	Company	2018	2024e
Tenapanor	Ardelyx	–	443
Linzess	Allergan	372	434
Movicol	Norgine	188	179

Analysts now forecast a launch in IBS-C in 2021. Given Linzess’s headstart, and the fact tenapanor has so far lagged on efficacy and adverse events, the latter will face a tough time achieving the $443m of IBS-C revenues expected in 2024. A partner could help Ardelyx drive sales, and the company has previously said it was in discussions; these could accelerate if tenapanor is approved.

If all of these catalysts turn out to be positive it could make for a year-end turnaround for Ardelyx, which has recently seen its shares fall by 15%.

Hungry for success

Meanwhile, Rhythm Pharmaceuticals is expected to announce topline data from two pivotal trials of its lead project, setmelanotide, in two ultra-rare genetic obesity disorders in the third quarter.

Patients with the diseases, homozygous pro-opiomelanocortin (POMC) deficiency and leptin receptor (LepR) deficiency, have insatiable hunger and suffer from obesity at an early age.

Setmelanotide is designed to activate the melanocortin-4 pathway, which should lead to increased energy expenditure and reduced appetite.

The primary endpoint of both studies is the number of setmelanotide-treated patients who achieve 10% reduction in weight from baseline after 52 weeks versus placebo. The studies also include a double-blind, placebo-controlled, eight-week withdrawal period to measure weight and hunger scores when the therapy is stopped.

If the results are positive a US filing could be on the cards for the end of 2019 or early 2020. So far, if phase II studies are anything to go by, the omens look good for approval. In phase II patients reported body weight reductions of 10-30% after 52 weeks, and setmelanotide has not demonstrated the cardiovascular side effects that have plagued previous MC4 receptor agonists.

However, even if setmelanotide succeeds in the clinic, its commercial chances look less clear, with questions remaining over the size of the market. Indeed, consensus sellside forecasts from EvaluatePharma put 2024 sales at just $47m.

https://www.evaluate.com/vantage/articles/events/upcoming-events/upcoming-events-pivotal-data-readouts-ardelyx-and-rhythm

Improved vaccine for bacterial meningitis and bloodstream infections

Researchers have now developed a new vaccine, a native outer membrane vesicle (NOMV) vaccine, for meningitis and bloodstream infections caused by “meningococcal group B” bacteria. This will allow younger people to be vaccinated and will address several limitations of the current vaccinations. The research is published this week in mBio, a journal of the American Society for Microbiology.

“We developed the improved version of the vaccine by making several genetic changes to the strain of bacteria used to produce the vaccine, resulting in a broadly protective vaccine rather than a strain-specific vaccine,” said Peter Beernink, Ph.D., Scientist at the Center for Immunobiology and Vaccine Development, Benioff Children’s Hospital Oakland.

There are currently only two licensed vaccines for prevention of meningitis and bloodstream infections caused by “meningococcal group B” bacteria, which are only licensed for use in people age 10 years and older. Both vaccines contain a bacterial protein known as Factor H binding protein (FHbp), which can bind to a host protein known as Factor H (FH). The licensed vaccines have several limitations, which include lack of effectiveness against some bacterial strains and low immune responses of infant humans.

The researchers immunized infant rhesus monkeys with the NOMV-FHbp vaccine, which induced higher levels of protective serum antibodies than a licensed vaccine against five of six bacterial strains tested. Two macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, developed antibodies to the host FH protein whereas none of the animals given the NOMV-FHbp vaccine or a negative control vaccine developed such antibodies.

The monkey antibody responses to the vaccines were measured in the laboratory based on the ability of serum antibodies to kill the bacteria in a test that is widely considered to predict protection in humans. The sample sizes of animals were chosen such that the results are highly statistically significant.

“The experimental NOMV vaccine extends the approach of using outer membrane vesicle vaccines, which previously have been given to millions of persons during meningitis B epidemics in Norway, Cuba and New Zealand,” said Beernink.

Thus, in a relevant infant non-human primate model, the NOMV-FHbp vaccine elicited higher levels of protective antibodies than the licensed vaccine and anti-FH antibodies in fewer animals. “This shows that the vaccine has the potential to be developed into a more broadly protective vaccine for humans, to extend coverage to infants and toddlers, which are the age groups among the highest risk of developing meningococcal disease, and to increase vaccine safety,” said Beernink.

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Story Source:

Materials provided by American Society for Microbiology. Note: Content may be edited for style and length.

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Journal Reference:

1. Peter T. Beernink, Vianca Vianzon, Lisa A. Lewis, Gregory R. Moe, Dan M. Granoff. A Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Mutant FHbp Elicits Higher Protective Antibody Responses in Infant Rhesus Macaques than a Licensed Serogroup B Vaccine. mBio, 2019; 10 (3) DOI: 10.1128/mBio.01231-19

https://www.sciencedaily.com/releases/2019/06/190628134819.htm

Brain cancer biotech CNS Pharma files, sets terms for $10 million IPO

CNS Pharmaceuticals, an early stage biotech developing therapies for brain cancer and other CNS tumors, announced terms for its IPO on Friday.

The Houston , TX-based company plans to raise $10 million by offering 2.1 million shares at a price range of $4 to $5. At the midpoint of the proposed range, CNS Pharmaceuticals would command a fully diluted market value of $77 million.

CNS Pharmaceuticals was founded in 2017 and plans to list on the Nasdaq under the symbol CNSP. The Benchmark Company is the sole bookrunner on the deal.

Relevant Profile: CNSP

https://www.renaissancecapital.com/IPO-Center/News/63981/Brain-cancer-biotech-CNS-Pharmaceuticals-files-and-sets-terms-for-$10-milli