Clinical Research In India

60 Years After The Thalidomide Crisis, We Finally Understand What Went Wrong

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It’s been nearly six decades since suspicions first arose that a common anti-nausea drug named thalidomide was responsible for shocking deformities in infants.

The tragedy now serves as an infamous reminder of the importance of clinical testing and strict drug regulation. But the mechanisms behind thalidomide’s side-effects have remained a mystery, until now.

Scientists at the Dana-Farber Cancer Institute in the US have discovered how thalidomide breaks down a surprising variety of proteins that control how genes are translated.

One of these transcription proteins – called sal-like protein 4 (SALL4) – plays a central role in holding embryonic stem cells in a blank state. Without it, tissues in developing embryos can fail to complete organs and limbs.

The discovery goes some way to explaining why many mothers who took the drug under commercial names such as Contergan or Distaval miscarried or delivered children who had malformed digits, limbs, or organs.

“The similarities between the birth defects associated with thalidomide and those in people with a mutated SALL4 gene are striking,” says pharmacologist Eric Fischer.

“They make the case even more strongly that disruption of SALL4 is at the root of the devastation produced by thalidomide in the 1950s.”

Thalidomide was first synthesised by a small German pharmaceutical company called Chemie Grünenthal early in 1954. Animal testing showed it wasn’t toxic at even large doses, and two years later it was found to be safe for adults as a sedative.

By the end of the decade the drug was sold worldwide under a variety of brand names, and commonly used to ease the nausea of morning sickness, but a delay in FDA approval spared the US from the tragedy that would unfold.

German physicians noticed a strange surge in infant deformities towards the end of the 1950s.

In 1960, a paediatrician named Widukind Lenz finally made the link, and after a public uproar, Grünenthal removed all thalidomide medications from the market.

The rest of the world was slower to act, but by the end of 1962 the product had all but disappeared from pharmacy shelves across the globe.

Though relatively brief, thalidomide’s period of popularity saw more than 120,000 infants affected. Most cases resulted in miscarriages, but around 10,000 babies were born with truncated arms and legs, or conditions such as Duane Radial Ray Syndrome.

Decades of lawsuits and media scrutiny of testing procedures have since examined the bureaucratic failures that contributed to the problem, but surprisingly little has been known about the biochemistry behind the drug.

This isn’t just a matter of easing morbid curiosity, either. In the 1980s, thalidomide was reborn in the form of a powerful cancer treatment, thanks to its ability to impede the growth of blood vessels in tumours.

The biochemistry behind the drug’s therapeutic effects has only been pinned down in recent years. Understanding the precise origins of its debilitating effects on tissue development will hopefully go a long way to overcoming its stigma.

Following on from previous research, researchers treated human cell cultures with thalidomide and its chemical relatives and looked through the protein products for signs of its impact using a mass spectrometry-based workflow.

Of 10,000-odd proteins in their analysis, only SALL4 showed a significant difference following each of the thalidomide-like drugs. This isn’t all that surprising, since mutations in both copies of the gene that makes this protein can produce similar conditions in foetal development.

What is interesting is different members of the drug family each degraded a variety of proteins – information that could prove useful in future modifications of the pharmaceutical.

In addition, the researchers found the effects of thalidomide only apply to primates (including humans) and rabbits, and not rodents. Testing on rats, in other words, would not show the same devastating results.

Thalidomide still has huge potential. Rather than walk away from a drug that could save lives, it’s vital we learn as much as we can about how it works.

“We know that the therapeutic effect of these drugs is based on their ability to degrade specific proteins,” says Fischer.

“Our findings will help drug developers distinguish between proteins whose degradation is likely to be beneficial and whose may be harmful.”

This research was published in eLife.

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Scientists Just Discovered a New Kind of Lung Cell Nobody Ever Knew About

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Two groups of researchers have independently discovered a new, rare type of lung cell.

These cells, which make up only 1 percent of all cells in the lung, express a large amount of the protein responsible for cystic fibrosis, which could help researchers develop brand-new treatments in the future.

Cystic fibrosis is a genetic disorder caused by mutations in both copies of a gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

CFTR is involved in the production and release of body fluids like mucus and sweat, and when the gene is non-functional, secretions that are usually thin become thick.

This is what causes a number of symptoms of the disease, including frequent lung and sinus infections.

“Cystic fibrosis is an amazingly well-studied disease, and we’re still discovering completely new biology that may alter the way we approach it,” said Jayaraj Rajagopal, senior author of one of the studies and medical doctor at Massachusetts General Hospital, Boston.

“We have the framework now for a new cellular narrative of lung disease.”

Both sets of researchers started by trying to build an atlas of the cells that make up the airway.

They analysed the gene expression of tens of thousands of individual cells, one at a time.

Once they’d been analysed, the teams were able to compare the gene expression patterns and catalogue the different cell types, states, abundance, and distribution through the airway.

One of the cells they identified had never been seen before, which they called a pulmonary ionocyte.

The standard wisdom when it comes to CFTR is that it is expressed at low levels in ciliated cells, a common lung cell type.

But the researchers found that this new pulmonary ionocyte has exceptionally high levels of CFTR expression, meaning that these cells – if mutated – could be causing cystic fibrosis.

Rajagopal’s team then disrupted a critical molecular process in the pulmonary ionocytes in mice, finding that some features associated with cystic fibrosis – like thick mucus – occurred.

Although this isn’t a definite confirmation that cystic fibrosis is caused by pulmonary ionocytes, it is a solid piece of research pointing in that direction.

And this is a big deal, according to Amy Ryan, a lung biologist at the University of Southern California, who was not involved in either study.

“These papers are extremely exciting,” says Ryan in an interview with The Scientist.

“They’ve interrogated the cellular composition and the cellular hierarchy of the airways by using a single-cell RNA-sequencing technique. That kind of information is going to have a significant impact on advancing the research that we can do, and hopefully the derivation of new therapeutic approaches for any number of airway diseases.”

The researchers hope they can look at a number of diseases with this new information and atlas of cells.

“So much that we found rewrites the way we think about lung biology and lung cells,” says Rajagopal.

“I think the entire community of pulmonologists and lung biologists will have to take a step back and think about their problems with respect to all these new cell types.”

The two papers have been published in Nature and can be viewed here and here.

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Roche’s RG6042 receives Prime designation from EMA to treat Huntington’s disease

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Roche announced that the European Medicines Agency (EMA) has granted Prime (PRIority MEdicines) designation for the company’s investigational medicine RG6042 (formerly known as IONIS-HTTRx) for the treatment of people with Huntington’s disease (HD).

RG6042 has demonstrated its ability to reduce the toxic mutant huntingtin protein (mHTT), which is believed to be the underlying cause of HD, in a phase I/IIa study. Prime is a designation implemented by the EMA to support data generation and development plans for promising medicines, providing a pathway for accelerated evaluation by the agency, and thus potentially enable them to reach patients earlier.

“We are very pleased that the European Medicines Agency has granted Prime designation for RG6042, as there is an urgent medical need to find treatment options for families affected by Huntington’s disease,” said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. “Preliminary data on RG6042 were the first to show that levels of toxic mutant huntingtin protein can be lowered in adults with Huntington’s disease, and we are working closely with the EMA and other health authorities to initiate a global phase III study as soon as possible.”

PRIME designation for RG6042 is primarily based on the data from an exploratory phase I/IIa trial of RG6042 that demonstrated a significant reduction in mHTT, which breaks down the nerve cells in the brain. The study demonstrated a mean 40% (up to 60%) reduction of the specific HD protein in the cerebrospinal fluid (CSF) of adult patients treated with RG6042 for three months at the two highest doses. Furthermore, levels of mHTT measured in the CSF were still declining in the majority of treated patients (70%) as of the last measurement in the study. RG6042 was well tolerated in this short initial study. These data were shared at the CHDI 13th Annual HD Therapeutics Conference in March 2018, and updated results were presented at the American Academy of Neurology (AAN) Annual Meeting in April 2018.

Roche will initiate a pivotal phase III study to evaluate RG6042 in a larger patient population to further characterise the safety profile and determine if it can slow the progression of HD in adults.

RG6042 is a second-generation modified antisense oligonucleotide (ASO) designed to reduce the production and levels of mHTT protein by targeting human HTT mRNA.5 RG6042 is the result of a comprehensive drug discovery programme between Roche and Ionis Pharmaceuticals focused on optimising the potency, specificity and tolerability of an ASO targeting human HTT mRNA. RG6042 is the most advanced compound in clinical development to target toxic mutant huntingtin protein (mHTT), which is believed to be the underlying cause of HD. Treatment with RG6042 has the potential to slow or stop disease progression in all people with HD.

Huntington’s disease is a rare genetic, progressive condition that causes the nerve cells in the brain to break down, which severely affects a person’s everyday functions such as mobility and thinking. It has a devastating impact on people living with the disease, and the hereditary nature of HD means it profoundly affects entire families. As the disease progresses, people with HD may develop personality changes, difficulty walking and swallowing, as well as having a significant cognitive impact. Survival ranges from approximately 10-20 years following motor onset of the disease.

There is no known cure for HD and no approved therapies that treat the underlying cause. The estimates for the number of people affected by Huntington’s vary between geographic regions. Huntington’s disease is the most common monogenic neurological disorder in the developed world, with an estimated prevalence of 3.5–7/100,000 in North America, Western Europe, and Australia.

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Even Being Just a Little Dehydrated Makes It Harder to Think, Study Reveals

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If you’re finding it hard to get your thoughts straight, dehydration could be to blame. An analysis of previous research has found a link between dehydration and poor performance in tasks that need serious focus or advanced mental processing.

While we know that staying hydrated is good for us for all kinds of reasons, this new meta-study was designed to take a closer look at exactly which brain processes might be affected and at what level of dehydration.

It turns out that at just a 2 percent level of body mass loss due to dehydration – so losing about a litre of water through sweat – the mental imbalance starts. That underlines how crucial it is for us to keep up our water intake, and how damaging it might be to the mental agility we all rely on if we don’t.

“We find that when people are mildly dehydrated they really don’t do as well on tasks that require complex processing or on tasks that require a lot of their attention,” lead researcher Mindy Millard-Stafford, from the Georgia Institute of Technology, told Allison Aubrey at NPR.

Millard-Stafford and her colleague Matthew Wittbrodt looked at 33 previous studies linking dehydration with mental performance. In total, the studies covered a total of 413 individuals experiencing between 1 percent and 6 percent of body mass loss through dehydration.

That 2 percent point seems to be the tipping point when it comes to staying mentally sharp. According to the experts, it would maybe take an hour’s hike to get to that level.

What’s more, it’s a level of dehydration that we might not actually notice through triggers like increased thirst: so mental performance could decline even when we don’t feel like we need to take on any water.

The analysis backs up previous research suggesting that dehydration impairs some mental processes more than others, with attention, executive function, and motor coordination particularly hard hit. Lower-level tasks like reaction time aren’t as badly affected, the meta-study shows.

While it’s different for every individual, experts recommend that women get up to 2.7 litres or 95 fluid ounces (11.5 cups) of water every day, and men up to 3.7 litres or 130 fluid ounces (15.5 cups).

The body as a whole is 60 percent water, which it leverages for jobs like transporting nutrients around the body and lubricating our eyeballs.

When there isn’t enough water available – it’s regularly lost through sweating and urination – these vital functions start to break down. We become thirsty, start to feel nauseous, and become more likely to feel exhausted.

There are limitations to the research, as there are with any meta-study like this: the individual studies analysed were all run with different people, under different conditions, and with different structures. That said, it does give researchers a framework to start investigating this link further.

Future research will be able to look at this framework in more detail. In the meantime, if you’ve got a lot of mental processing to do, make sure you drink plenty of water first.

The research has been published in Medicine & Science in Sports & Exercise.

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Mologic starts clinical trial of urine-based diagnostic for cystic fibrosis

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Mologic Ltd, a developer of powerful, personalised diagnostics to improve the lives of patients, announced that it has commenced a clinical trial to evaluate the Company’s urine-based diagnostic, HeadsUp, in monitoring pulmonary exacerbation in cystic fibrosis (CF) patients. The study aims to identify five urinary biomarkers associated with the onset of pulmonary exacerbation in adults with CF. It will also validate the use of the novel point-of-care (POC) test for patient’s self-monitoring of their condition.

Patients will be recruited from the West Midlands Adult CF Centre, Birmingham, UK where they are under the care of the trial’s Principal Investigator, Dr Edward Nash. As one of the largest CF units in the UK, the centre currently provides care for at least 360 adults with CF.

The test is based on regularly measuring five different biomarkers in urine and using an app-imbedded algorithm to convert data to a traffic light ‘RAG’ result, indicating whether the patient is stable or in need of medical intervention. As a two-phase study, phase 1 requires participants to perform a number of regular physiological tests as well as providing a daily urine sample to Mologic. Analysis of the sample will confirm which of the urinary biomarkers already identified, are the key five associated with the onset of pulmonary exacerbation. In phase 2, patients will be asked to perform the test daily to validate the selection of biomarkers and also provide information about the usability of the system.

Professor Paul Davis, Mologic cofounder and Chief Scientific Officer commented: “Our aim has been to develop a simple, non-invasive test that helps patients suffering from chronic lung disease to understand, monitor and manage their condition at home. We have identified the biomarkers in urine that reflect critical changes in the lung and are linked with the onset of an attack. Using the techniques underlying a standard pregnancy test, the CF HeadsUp device can measure a subset of these biomarkers and transform the data into straightforward actions and medications. We now look forward to clinical trials and working with the West Midlands Adult CF Centre to build evidence and refine the tests through patient feedback.”

Dr Edward Nash, Chief Investigator and CF Consultant: “For people who suffer from a chronic lung disease such as CF, there is an ever-present risk of recurrent lung attacks (exacerbations) during which every breath can be a struggle. HeadsUp is non-invasive and allows frequent testing in the home, empowering patients to take control of their condition, which has the potential to reduce lung damage and avoid stays in hospital.

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