Category Archives: Transhuman News

The Food and Drug Administration has halted a clinical trial of Novartis Zolgensma gene therapy due to a safety concern found in an animal study, the company said Wednesday.

The hold affects the Novartis (NVS) clinical trial known as STRONG, which was testing a higher dose of Zolgensma administered by spinal injection to older children with spinal muscular atrophy (SMA). It does not affect the already approved treatment of infants and children.

Novartis said its subsidiary AveXis informed regulators about findings from an animal study that showed dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss. The clinical significance of this adverse safety signal is not known, but it can be associated with sensory effects, the company added.

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Halting the STRONG clinical trial is a setback for Novartis effort to expand the use of Zolgensma to older patients with SMA. Biogens Spinraza treatment is already approved for older SMA patients. Roche (RHHBY) is expected to secure approval of its own SMA treatment next year.

Novartis said it has seen no reports of sensory effects in patients and is working with the FDA to resolve safety concerns and resume dosing of Zolgensma in the clinical trial.

The FDAs action on Wednesday follows a controversy involving manipulation of data used to support Zolgensmas approval. In an unusual rebuke, the agency said in August that AveXis knew that preclinical data had been falsified before the drug was approved in May, but did not inform the agency until later. The agency said that the drug should stay on the market, but the scandal sparked anger from lawmakers and a pledge from Novartiss CEO, Vas Narasimhan, to move more quickly on disclosing issues around data integrity.

Zolgensma carries a price tag of $2.1 million, making it the worlds most expensive medicine. Earlier this month, Novartis said the gene therapy had been used to treat 100 patients since its launch and brought in $160 million in the third quarter, beating analysts expectations.

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Novartis' Zolgensma gene therapy study halted on animal safety concerns - STAT

KENDALLVILLE Eighteen-month-old Omarion Jordan plays with his toys in his Kendallville home under the watchful eye of his mother, Kristin Simpson, and the family dog. He's wiggly and active, with no hint of the rare genetic disease that could have taken his life before age2.

Omarion has a rare genetic disorder called severe combined immunodeficiency syndrome, SCID for short and better known as the bubble boy disease made famous in a 1976 television movie starring John Travolta as well as an episode of the 1990s sitcom Seinfeld. The disease affecting 40 to 100 American newborns each year makes them extremely vulnerable to infections, which left untreated, kills most children before they turn two. Simpson said SCID is caused by a random gene mutation on the maternal side. She said she has no family history that would indicate it was present in family members.

Omarion was born normally, but began to have skin infection symptoms before he was 3-months-old, she said. Doctors thought he had an extreme case of eczema or cradle cap.

Simpson said everything changed when Omarion got his 3-month vaccinations.

He had a bad reaction. He had no immune system to react with the vaccine, she said. He was covered in a green, pus-like substance.

Simpson took Omarion to the emergency room twice, but was sent home. She then made an appointment with her pediatrician, not knowing then that it would be months before she saw her apartment again.

The pediatrician sent us right to the hospital, Simpson said. It was 11/2 weeks to clear the infection. I had to drop everything. I never came back (to the apartment) after that morning.

Doctors sent Omarion and his mother on a four-hour ambulance ride to Cincinnati Children's Hospital for tests. There, Simpson learned that the standard treatment for SCID was a bone marrow transplant. When a two-month search for a bone marrow match came up empty, doctors suggested another route.

There was a trial at St. Jude (Children's Hospital) for gene therapy and we were given the option, Simpson said. We were flown to St. Jude's on a private jet.

The experimental gene therapy used Omarion's own bone marrow, altered to correct the missing gene. The altered bone marrow is transplanted back into Omarion's body, carried by an HIV virus with all the harmful cells removed.

It's like a car, Simpson said. They take out the harmful elements and use the virus as a carrier for the altered gene.

Experimental gene therapy comes with both reward and risk. The treatment could be a breakthrough cure for Omarion and other children affected by the gene mutation.

The risks include developing leukemia, which has happened to some patients in the small trial group, other unknown side effects and the enormous financial cost. Treatment costs run into the millions of dollars.

Gene therapies, while breaking new ground in fighting tough-to-cure ailments, are a cutting edge field of medicine, but also an exceptionally expensive one. For example, a gene therapy drug called Zolgensma is the most expensive drug ever approved in the United States, according to a Bloomberg Businessweek story about Omarion and the rise of gene therapies. A one-time infusion costs $2.1 million.

Omarion's case has received national media attention, including the story from Bloomberg Businessweek, which published a story June 5 about the balance of rapidly progressing gene therapy and its high cost, and other outlets including NBC News, WebMD.com and CNN Health.

Simpson is grateful that St. Jude's Children Hospital, the world's leader in the treatment of childhood diseases, has picked up the entire tab for Omarion's treatment.

Simpson said that at St. Jude, she and her mother were the only family members allowed inside Omarion's isolation room. Everyone else was fully masked and gowned. They were in the isolation room for months.

Omarion received his bone marrow transplant Dec. 20, 2018, and finally left the hospital in April. Omarion will have checkups every three months for the foreseeable future and an annual checkup for the rest of his life.

Today he's healthy, thanks to a cutting-edge gene therapy treatment, and a walking miracle.

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Gene therapy gives toddler second chance | Indiana | Journal Gazette - Fort Wayne Journal Gazette

Fighting Blindness Canadas secure, clinical patient registry is a database dedicated to connecting people living with retinal eye diseases to clinical trials and research.Paffy69 / PNG

Blind and partially sighted people no longer have to wait passively for a research breakthrough in hope of treatment options. In fact, people living with genetic eye conditions can now actively drive vision research forward by enrolling in a patient registry and getting their genes tested.

There are 2.2 billion people living with visual impairment globally. Some are living with inherited retinal diseases that are progressive and can lead to complete blindness. Up until recent years, blind and visually impaired people were told that no treatment is available. This is changing as genetic testing is paving the way for a surge of gene therapies.

My doctoral dissertation at the University of B.C. was on drug therapy for retinitis pigmentosa. This progressive, blinding eye condition is the most common type of inherited retinal disease.

In people affected by retinitis pigmentosa, the light sensing cells in their retina photoreceptors die early. Unlike skin cells that regenerate, the body does not make more photoreceptors once they are damaged.

As a vision scientist affected by retinitis pigmentosa, I am passionate about finding the truth about the disease. Why do photoreceptors die? How can we stop it? How can science and medicine help?

When I was 12 years old, I realized while at summer camp that my night vision was disappearing. In the last two decades, I lost my peripheral vision, contrast sensitivity and depth perception.

I worked in Dr. Orson Moritzs lab at the UBC department of ophthalmology and visual sciences, which focuses on research using tadpoles that contain known human mutations for retinitis pigmentosa to understand the disease.

I made an alarming discovery in our animal model: knowing the genetic cause of retinitis pigmentosa is vital for treatment with one class of drugs histone deacetylase inhibitors. These determine how genes are switched on or off.

A similar study in mice showed that the same drug reacted differently to variations in a single mutant gene that also causes retinitis pigmentosa.

Treating retinitis pigmentosa is like extinguishing fire. To stop a fire, you need to know whether its water-based or grease-based. If you try to use water to stop a grease fire, the damage gets worse.

Blind and visually impaired people can advocate for eye health by enrolling in a patient registry. Participation in a registry benefits researchers by offering more information about the disease.

In Canada, individuals can self-refer to Fighting Blindness Canadas secure, clinical patient registry. This database is dedicated to connecting people living with retinal eye diseases to clinical trials and research.

When a gene therapy trial arises, researchers draw participants from this database. Since gene therapy aims to correct an underlying genetic mistake in DNA that causes disease, knowing the genetic cause of a disease is a criteria for most gene therapy trials.

Globally, other registries include My Retina Tracker in the United States, Target 5000 in Ireland, MyEyeSite in the United Kingdom, the Australian Inherited Retinal Disease Registry and Japan Eye Genetics Consortium. In New Zealand, Dr. Andrea Vincent has established the Genetic Eye Disease Investigation Unit. There is even a Blue Cone Monochromacy Patient Registry for one rare eye condition.

In the last two decades, the number of gene therapy trials has blossomed. Currently, 250 genes on inherited retinal diseases have been identified. In 2017, the first gene therapy for inherited retinal disease Luxturna was approved by the United States Federal Drug Administration.

To date, there are trials for: retinitis pigmentosa; Usher syndrome, a condition that involves hearing and vision loss; achromatopsia, a disease that causes colour blindness; X-linked retinoschisis, a dystrophy that causes splitting of the retina and affects mostly in males; and age-related macular degeneration, the third-largest cause of vision loss worldwide, caused by the interplay between genetics and environment.

Enrolment in a patient registry and genetic testing advance the design of gene therapy trials. This in turn benefits blind and visually impaired people.

Research advancement is a concerted effort across the globe blind and partially sighted people should know they have the power to push it forward.

Ruanne Vent-Schmidt is a PhD candidate in cell and developmental biology at the University of B.C.This article originally appeared online at theconversation.com, an independent source of news and views, from the academic and research community.

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Ruanne Vent-Schmidt: The blind and visually impaired can help researchers by getting their genes tested - Vancouver Sun

In a recent monologue, the comedian James Corden addressed his struggles with being overweight. Despite his best efforts, he said, he has never been able to control his weight confessing that he has good days and bad months. The monologue was a response to an on-air editorial by Bill Maher, who argued that fat shaming needs to make a comeback, excoriating the obese for their lack of self-control. Which of them was correct? Are the obese to blame for their condition?

No. Recent research has revealed that obesity is to a very large extent encoded in our genes. Indeed, studies of identical twins reveal that the heritability of obesity ranges between 7080 percent, a level that is exceeded only by height and is greater than for many conditions that people accept as having a genetic basis. While there has also been an overall increase in the prevalence of obesity over the last several decades, it is the particular set of weight-regulating genes that a person inherits that determines who is lean and who is obese in 2019 America.

Could it be then, as Maher implies, that thin people control their urge to eat and the obese do not? For those who believe that being thin is a result of greater self-control, consider the case of a massively obese four-year-old boy in England, who weighed 80 pounds. After consuming a single test meal of 1,125 calories (half the daily intake of an average adult), he asked for more. This boy had a similarly affected eight-year-old cousin who weighed more than 200 pounds. Both children carry a genetic defect causing their obesity that runs in the family. The defective gene encodes the adipocyte hormone leptin, and the children do not produce it.

However, when they receive leptin injections, their appetite is reduced to normal, and they lose enormous amounts of weight. The boy in fact is now quite thin. These findings confirm that biologic factors play the key role in determining ones appetite undercutting the common misconception that food intake is primarily under voluntary control.

In normal people without leptin mutations, the hormone is secreted by fat cells into the bloodstream and then acts on specialized brain cells that regulate appetite. When the amount of fat increases, leptin production increases, and food intake goes down. When weight is lost, leptin decreases, which then stimulates appetite. This physiologic system acts in a manner analogous to a thermostat (or lipostat) that maintains body weight within a relatively narrow range.

This system serves a vital evolutionary function by maintaining optimal levels of adipose tissue, thus providing a source of calories when food is not available, a not uncommon occurrence during human evolution. However, the decreased mobility associated with excess fat can increase the risk posed by predators. The leptin system appears to have evolved to balance the risk of being too thin (starvation) and the risk of being too obese (predation). Indeed, the weight of all mammals is precisely regulatednotwithstanding that only humans have ever expressed a conscious desire to lose weight.

Specific genetic differences that predispose to obesity or leanness are then propagated by natural selection depending on whether starvation or predation was the greater risk. The weight of each individual is then stably maintained by the leptin system with remarkable precision. The average person takes in a million or more calories per year, maintaining weight within a narrow range over the course of decades. The body balances calorie consumption with expenditure, and with accuracy greater than 99.5 percenta precision far greater even than that on labels showing the calorie content of the food we eat.

Mutations in hormones are rare and there are only a few dozen patients who fail to produce leptin. So, while studies of these individuals establish a role for leptin to control appetite in human, defects in the gene itself are a very infrequent cause of obesity. However, mutations in the neural circuit that is regulated by leptin are more common, including mutations in the receptor for leptin. Patients with mutations cannot receive leptins signal and so also become massively obese. But because these patients cannot receive leptins signal, treatment with the hormone is ineffective and these patients are referred to as being leptin resistant.

The leptin receptor is expressed in the hypothalamus, a primitive part of the brain that regulates most basic biologic drives, including the basic drive to eat. In the hypothalamus, there are specialized neurons expressing the leptin receptor that regulate appetite. One type promotes food intake; a second neural population reduces food intake. Leptin acts by inhibiting the one and activating the other. Similar to mutations in the leptin receptor, mutations in other key genes downstream of the hypothalamus also cause human obesity. Recent genetic studies have shown that as many as 10 percent of markedly obese children carry mutations in one or another of these individual genes. Thus, when Maher categorically asserts that obesity isnt a birth defect, he is (mostly) wrong.

Another mistake that Maher and others make is to assume that the drive to eat is the same for all. Leptin regulates the intensity of the feeding drive. In its absence, patients report being unable to control their appetite and eat voraciously. One patient described it as hunger without end, akin to the hungriest youve ever been. That is how leptin deficient people feel all the time. This sensation appears to be similar for obese patients who lose weight (e.g., The Biggest Loser), the majority of whom put the weight back on

In aggregate, the genes that control food intake and metabolism act to keep weight in a stable range by creating a biological force that resists weight change in either direction. Moreover, the greater the amount of weight that is lost, the greater the sense of hunger that develops. So, when the obese lose large amounts of weight by conscious effort, their bodies fight back with a vengeance. If you think it is difficult to lose15 pounds, imagine what it must feel like to lose 50 or 100!

Can willpower restrain this drive over the long term? The evidence says that for the vast majority of people the answer is no. Yes, a relatively small proportion of patients do maintain long term weight loss. But willpower is not metaphysical, it is encoded in our cerebral cortex, where conscious thought resides. How the cortex successfully communicates with the hypothalamus varies among individuals. The precise ways that this communication happens is not yet known but is an area of active investigation.

What we do know tells us that if you are thin, you should thank your "lean" genes and refrain from stigmatizing the obese. A broad acceptance of the biologic basis of obesity would not only be fair but would allow us to collectively focus on health. Even modest amounts of weight loss, far less than would satisfy Maher, can improve health and this should be the objective for obese people who suffer from its medical complications.

While research is moving toward developing effective therapies for obesity, we are not there yet. In the meantime, we must change our attitudes and turn our focus from appearance and to improved health. The obese are fighting against their biology. But they also are fighting against a society that wrongly believes that being fat is a shameful, personal failing.

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Obesity Is in the Genes - Scientific American

Your genes can effect how you respond to medicine. Genetic testing can help identify the right drug at the right dose for a patient. Courtesy of Mayo Clinic

Predicting whether a patient like KerriePrettitorewill have a fatal reaction to a chemotherapy drug or even whether adrugwill work at all is the future of medicine, and its coming soon.

Genetic testing can help predict how patients will respond to a drug,whether its designed to combat cancer or other illnesses. Eventually, that will enable doctors to individualize patient treatment, choosing a medication and dose to best match a patients genetic profile. The goal is to maximize benefit while minimizing harm.

Research inseveral areasalready is having an impact:

KerriePrettitore, a Ridgewood woman,suffered from a genetic abnormality called DPD deficiency, which prevents someone from breaking down the chemotherapy drug 5-FU, or fluorouracil.Agenetic test can help identify patients who may be at risk of developing such a reaction.

Frances national drug-regulating agency began recommending last year that all patientsprescribed5-FU and related drugs be screened for DPD deficiency beforehand. Two hundred people a year die in France because they receive the drug and have DPD deficiency, according to a company that performs such tests. The company recommends that the genetic test be combined with a blood test for maximum accuracy, a practice that has been used in the Netherlands for almost a decade.

In theUnited States, testing for DPD deficiency is not currently recommended by major cancer treatment organizations.But some scientists say change will come soon.

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Genetic testsmust be inexpensive,produce results quickly and provide clinically useful informationto be cost-effective, said RobertDiasio, an authority on DPD deficiency and director of the Mayo Clinic Cancer Center. The tests currently availablefor DPD deficiencydont yet meet that standard, he said.

The testsdont identify everyone atrisk,and they may identify a mutation in a person who turns out to be able to tolerate the drug, he said. Thats because they test for only a handful of mutations. They dont testfor all possible mutations because it is expensive andyieldsinformation that scientists dont yet know how to interpret.

But the cost of a complete genetic analysis is coming downandthe turnaround time is getting quicker, he noted. Moreknowledge is needed, however,about which mutations are important and which are irrelevant to doctorsmakingprescribing decisions,Diasiosaid.

At the Mayo Clinics Center for Individualized Medicine,astudy of 10,000 Minnesota patientsis underway. It will integratepatients genetic informationinto theirelectronic medical recordsto inform physicians about significant linkages when certain medications are prescribed.

As research advances, more linkages will be discovered and included in the individual records. The goal isto help patients get the right drug at the right dose for their disease personalized medicine at its best.

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Does drinking more alcohol shrink the brain, or does a smaller brain volume actually predispose individuals to drink more alcohol?

Excessive alcohol consumption carries many risks, including heart and liver problems, a higher risk of cancer, and even brain damage.

Research has suggested that there is an association between high alcohol intake and reduced white and gray matter in the brain.

So far, most specialists have maintained that alcohol consumption leads to this decrease in brain volume, but could that conclusion be wrong?

Recently, a team of investigators from Washington University in St. Louis, MO, and Duke University in Durham, NC, has conducted a study that suggests that alcohol may not be the culprit behind lower brain volume.

Instead, the findings indicate that both reduced brain volume and a predisposition toward consuming higher quantities of alcohol may have the same underlying cause: genetic makeup.

"Our results suggest that associations between alcohol consumption and reduced brain volume are attributable to shared genetic factors," says senior author Ryan Bogdan.

"Lower brain volume in specific regions may predispose a person to greater alcohol consumption," he goes on to note.

"The study is impressive because it uses a variety of approaches and data analysis techniques to reach findings that all converge on the same conclusion," Bogdan also adds.

In the study the findings of which appear in the journal Biological Psychiatry the researchers analyzed the data from three separate brain imaging studies. These studies included one that recruited twins and non-twin siblings with different alcohol intake behaviors and one that involved children who had not had exposure to alcohol at baseline.

In the third study, the researchers had conducted analyses to determine gene expression in the brain using tissue samples that they had collected postmortem from donated organs.

In total, the investigators had access to data on 2,423 individuals. The three studies that the researchers accessed the data through were: the Duke Neurogenetics Study, the Human Connectome Project, and the Teen Alcohol Outcomes Study.

"Our study provides convergent evidence that there are genetic factors that lead to both lower gray matter volumes and increased alcohol use," says lead author David Baranger.

More specifically, the team found that individuals who had a higher alcohol intake had lower gray matter volume in the dorsolateral prefrontal cortex and the insula, which are two brain regions that play key roles in emotion, memory retrieval, reward cycles, and decision-making.

The researchers noted that, according to their analysis, lower gray matter in these two brain regions was actually due to a specific genetic makeup, which, in turn, was also associated with an increased risk of higher alcohol consumption, both in adolescence and in young adulthood.

"These findings don't discount the hypothesis that alcohol abuse may further reduce gray matter volumes, but it does suggest that brain volumes started out lower to begin with," Baranger clarifies.

"As a result," he adds, "brain volumes may also serve as useful biological markers for gene variations linked to increased vulnerability for alcohol consumption."

In the conclusion to their study paper, the investigators note that we should, perhaps, pay more attention to genetic risk factors when assessing the risk for higher alcohol consumption.

They write:

"Taken alongside evidence that heavy alcohol consumption induces gray matter volume reductions, our data raise the intriguing possibility that genetically-conferred reductions in regional gray matter volumes may promote alcohol use from adolescence to young adulthood, which may, in turn, lead to accelerated atrophy within these and other regions."

Moreover, the authors note that although the current findings relate specifically to alcohol consumption, they could also apply to the risk of using other substances, which the same genetic risk factors may drive.

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Alcohol intake and reduced brain volume: What explains the link? - Medical News Today

Nathaly Sweeney, a neonatologist at Rady Children's Hospital-San Diego and researcher with Rady Children's Institute for Genomic Medicine, attends to a young patient in the hospital's neonatal intensive care unit. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

Nathaly Sweeney, a neonatologist at Rady Children's Hospital-San Diego and researcher with Rady Children's Institute for Genomic Medicine, attends to a young patient in the hospital's neonatal intensive care unit.

When Nathaly Sweeney launched her career as a pediatric heart specialist a few years ago, she says, it was a struggle to anticipate which babies would need emergency surgery or when.

"We just didn't know whose heart was going to fail first," she says. "There was no rhyme or reason who was coming to the intensive care unit over and over again, versus the ones that were doing well."

Now, just a few years later, Sweeney has at her fingertips the results of the complete genome sequence of her sickest patients in a couple of days.

That's because of remarkable strides in the speed at which genomes can be sequenced and analyzed. Doctors who treat newborns in the intensive care unit are turning to this technology to help them diagnose their difficult cases.

Sweeney sees her tiny patients in the neonatal intensive care unit of Rady Children's Hospital in San Diego. Doctors there can figure out what's wrong with about two-thirds of these newborns without a pricey DNA test. The rest have been medical mysteries.

"We had patients that were lying here in the hospital for six or seven months, not doing very well," she says. "The physicians would refer them for rapid genome sequencing and would diagnose them with something we didn't even think of!"

Rady's Institute for Genomic Medicine, which has been pioneering this technology, has now sequenced the genomes of more than 1,000 newborns.

In a building across the street from the hospital, three $1 million sequencing machines form the core of the operation. Technicians tending to the NovaSeq 6000s can put DNA from babies (and often their parents) into the machine in the late afternoon and have a complete genome sequence back by 11 a.m. or noon the next day, says clinical lab scientist Luca Van der Kraan.

That fact is worth repeating: An entire genome is decoded in about 16 hours.

Kasia Ellsworth is one of the experts waiting in a nearby office to analyze the information. That task has shrunk from months to typically just four hours, thanks to increasingly sophisticated software.

Ellsworth inputs the baby's symptoms into the software, which then spits out a long list of genetic variants that might be related to the illness. She scrolls down the screen.

"I'm looking through a list of those variants and then basically deciding whether something may be truly contributing to the disease or not," she says.

About 40% of the time, a gene stands out, giving doctors a tentative diagnosis. Follow-up tests are often requested, and those can take several days. But in the meantime, doctors can sometimes act on the information they have in hand.

When she or a colleague makes a diagnosis, "You always feel very relieved, very happy and excited," she says. "But at the same time you kind of need to put it in perspective. What does it mean for the family, for the patient, for the clinician as well?"

Often it's a sense of relief. And for a minority of cases, it can affect the baby's treatment.

"We now are at the point where I think the evidence is overwhelming that a rapid genome sequence can save a child's life," says Dr. Stephen Kingsmore, the institute's director and the driving force behind this revolution.

By his reckoning, the results change the way doctors manage these cases about 40% of the time.

Treatments are available for only a small share of these rare diseases. In other cases, the information can help parents and doctors understand what's wrong with their baby even if there is no treatment or learn whether death is inevitable. "And there it's a very different conversation," Kingsmore says. "We help guide parents through picking an appropriate point at which to say enough is enough" and to end futile treatments.

Of course, Kingsmore highlights the happier outcomes. One example is a bouncy girl named Sebastiana, now approaching her third birthday.

As a newborn, Sebastiana Manuel was diagnosed with a rare disease after rapid genome sequencing. She is seen here at 11 months of age. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

As a newborn, Sebastiana Manuel was diagnosed with a rare disease after rapid genome sequencing. She is seen here at 11 months of age.

He showed off her case recently in front of the Global Genes conference, a meeting of families with rare genetic conditions.

"She was critically ill in our intensive care unit," he tells the audience, "and in a couple of days we gave the doctors the answer. It's Ohtahara syndrome. It comes with this specific therapy. And she hasn't had a seizure in 2 1/2 years. She doesn't take any medication."

The audience applauds enthusiastically at an outcome that sounds miraculous. But when you meet Sebastiana and her mother, Dolores Sebastian, a more complicated story emerges.

Ohtahara syndrome isn't actually what made Sebastiana ill it's a term doctors use to describe newborn seizures. Those are actually a symptom of deeper brain issues. That was apparent the day she was born.

"She was acting weird and screaming and crying and turning purple and we weren't sure why," her mother says.

The hospital where Sebastiana was born rushed her to the neonatal intensive care unit, across town at Rady. She was having frequent seizures. The following days were a nightmare for Sebastian and her husband.

"I can't even describe it," she says. "I always keep on saying that at that moment I was kind of like dead, but I was walking."

The hospital ran a battery of tests to look for severe brain damage. They couldn't get to the bottom of it.

"They came in and offered us the genomic testing," Sebastian said. "They never told us how quick it would be."

She was surprised when the results were back in four days. The doctor told her they had identified a gene variant that can trigger seizures as well as do other harm to the brain.

"He said this is how we're going to go ahead and change her medications now and treat her," she says. And that made a "huge difference, [an] amazing difference."

Sebastiana was already on a medication that was helping control her seizures, but they sedated her to the extent that she needed a feeding tube. On the new medication, carbamazepine, she was alert and able to eat, and her seizures were still under control. Sebastian says her daughter is still taking that drug.

Controlling her seizures isn't a cure. Children who have this genetic variant, in a gene called KCNQ2, can have a range of symptoms from benign to debilitating. Sebastiana falls somewhere in between. For example, she has only a few words in her vocabulary as she approaches the age of 3.

"She took her first steps when she was 2 years old, so she's delayed in some things," Sebastian says, "but she's catching up very quickly. She has [physical therapy]; she's going to start speech therapy. She gets a lot of help but everything's working."

Sebastiana Manuel (second from left) with members of her family: Domingo Manuel Jr. (from left), Dolores Sebastian and Tony Manuel. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

Sebastiana Manuel (second from left) with members of her family: Domingo Manuel Jr. (from left), Dolores Sebastian and Tony Manuel.

KCNQ2 variants are the most common genetic factor in epilepsy, causing about a third of all gene-linked cases and about 5% of all epilepsies. Sebastiana's case could have been diagnosed with a less expensive test. For example, Invitae geneticist Dr. Ed Esplin says his company offers a genetic screen for epilepsy that has a $1,500 list price and a two-week turnaround.

Rady's whole-genome test costs $10,000, Kingsmore says. But it casts a wider net, so it might provide useful information if a baby's seizures are caused by something other than epilepsy.

And Kingsmore says his test costs about as much as a single day in the NICU. "In some babies we avoid them being in the intensive care unit literally for months," he says.

Kingsmore and colleagues have published some evidence that their approach is cost-effective, based on an analysis of 42 cases.

Even so, most insurance companies and state Medicaid programs are still balking at the cost. Kingsmore says private donors are helping support this effort at Rady, which sequences about 10% of the babies in the NICU, and at more than a dozen others scattered from Honolulu to Miami. They send their samples to Rady for analysis.

Kingsmore is pushing to expand his network in the next few years, to reach 10,000 babies at several hundred children's hospitals.

Other providers are also starting to offer whole-genome sequencing. But Dr. Isaac Kohane, chair of the department of biomedical informatics at Harvard Medical School, worries that the technology is too unreliable.

Knowledge of genes and disease is evolving rapidly, so these analyses run the risk of either missing a diagnosis or making a mistaken one. Kohane says there's still a lot of dubious information there a typical person has 10 to 40 gene variants that the textbooks incorrectly identify as causing disease.

Kohane is part of a medical network that helps diagnose people with baffling diseases. A study from 2018 found "a third of the patients who actually come to us already had full genome sequences and interpretations," Kohane says. "They were just not correct."

Even so, Kohane sees this use in the NICU as a relatively fruitful use of gene sequencing. "This is one of the few areas where I think the Human Genome Project is really beginning to pay off in health care," he says, "but buyer beware, it's not something ready to be practiced in every hospital." (He supports the work at Rady in fact, he is a science adviser.)

Kingsmore is already looking ahead. "We want to solve the next bottleneck, which is, 'I don't have a great treatment for this baby,' " he says. That's a far greater challenge, and it's especially difficult for a mutation that has altered a baby's development in the womb. Those problems may often not be reversible.

Kingsmore is undeterred. "It's going to be an incredibly exciting time in pediatrics," he says.

You can contact NPR science correspondent Richard Harris at rharris@npr.org.

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Genome Sequencing In NICU Can Speed Diagnosis Of Rare Inherited Diseases : Shots - Health News - NPR

In celebration of our 15 Year Anniversary, Academic Editor Ronald CW Ma highlights advancements published in PLOS Medicine in diabetes research and care, including improved precision medicine.

Happy 15th Birthday to PLOS Medicine! I still remember reading about the PLOS journals and the idea of making science accessible to all back when PLoS was first launched. It is amazing how far the Open Access movement has developed, how far that idea has advanced and how scientific publishing has been revolutionized. Congratulations PLOS Medicine on this important milestone!

Among the many articles that I have enjoyed reading in PLOS Medicine over the years, I would like to highlight two for sharing with other readers on this special occasion.

1) Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis

This paper by Philip Clarke and colleagues from the ADVANCE Collaborative Group, published back in 2010, highlighted the significant economic burden of diabetes and rates of hospitalization resulting from diabetes co-morbidities, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a landmark multi-centre trial on the treatment of diabetes conducted in 20 countries. Within the ADVANCE trial settings, the study demonstrated important differences in the rates of hospitalization for different diabetes complications in different regions of the world (Asia, Eastern Europe, and established market economies such as Australia, New Zealand and Canada), mirroring epidemiological observations of comparative higher nephropathy rates, higher stroke risk, and lower risks of coronary artery disease among Asians (mostly from Chinese centres in this particular trial) with type 2 diabetes, thereby highlighting the heterogeneity of risk of diabetes complications (and costs) in different populations.

This study also provided important tools to facilitate estimation of healthcare expenditure associated with diabetes in different healthcare settings. At the time of the study, it was estimated that the average annual per capita health expenditure was approximately 216 international dollars in China, and 698 international dollars in Russia, but that the annual hospital costs for people with diabetes experiencing major macrovascular complications such as coronary or cerebrovascular events would be around four and ten times these average per capita expenditures. Perhaps not fully appreciated at the time was the significant burden associated with hospitalization with heart failure, which is a topic of much current interest in relation to recent advances in the treatment of type 2 diabetes.

Although the work was focused on evaluating the economic burden of diabetes in different parts of the world, this work can be considered as an important example of early attempts to deconstruct the heterogeneity of type 2 diabetes. As the diabetes epidemic continues unabated, the healthcare burden of diabetes complications has become a major concern globally.

2) Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

The second article, by Jose Florez and colleagues, utilized a state-of-the-art multi-omics approach to use available genetic and epigenomic data to probe the issue of heterogeneity of diabetes. The authors showed that identified genetic loci linked to diabetes can be segregated according to underlying biological mechanisms which can be used to classify individuals, to provide a way forward for individualized diagnosis, monitoring and treatment. The study highlighted the potential role of genetic variants related to the beta cell, pro-insulin, obesity, lipodystrophy and liver/lipid traits in accounting for different patient characteristics, as well as long-term diabetes outcomes.

What was particularly interesting is the soft-clustering approach adopted by the authors, which did not require genetic variants to fit into only one pathway, or for individuals to be classified to have diabetes due to only one specific pathophysiological defect, but instead, for individuals to be identified to have scores in each of the above-mentioned categories, and thereby accepting that individuals may have developed diabetes with different contribution from the different underlying pathophysiology. The use of such genetic risk scores may be useful in selecting the most appropriate therapies for individualized care in the future.

Over the last 15 years, the global burden of diabetes has more than doubled, from less than 200 million people affected back in the early 2000s to now more than 422 million people affected globally (with the majority in LMICs). These 2 articles represent important advances in our understanding of type 2 diabetes over the last decade. Whilst the ADVANCE study was a landmark study that generated much interest, the Clarke paper highlighted much of the burden of diabetes complications, and our lack of understanding regarding the heterogeneity in risk of diabetes complications. Together with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Trial (VADT) studies, these landmark studies, published between 2008-2010, have highlighted the potential dangers of hypoglycaemia, and heralded the debate and call for more individualized treatment in type 2 diabetes, and contributed to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) to propose in their joint position statement on management of hyperglycaemia in type 2 diabetes in 2012 to move away from a one-size-fit-all approach to treatment, but instead adopt a treatment strategy that is more tailored to individual patient profile, disease duration, co-morbidities and expectations. This represented a major watershed moment in the evolution of diabetes research and care.

With recent advances in genomic medicine and the genetics of type 2 diabetes, some of which have been reported in PLOS Medicine, the era of precision medicine in diabetes is very much here to stay. We, as diabetes researchers and clinicians caring for people with diabetes, look forward to further advances in our understanding of how best to treat individuals with diabetes based on their underlying genetics, pathophysiology, and needs, and to improving outcomes for people with diabetes.

Congratulations again PLOS Medicine and we look forward to the next 15 years of exciting advances!

Ronald Ma is Professor and Head of Division of Endocrinology and Diabetes at the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, and co-lead of the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine. He is a member of the Executive Board, Asian Association for the Study of Diabetes (AASD), and member of the editorial board of PLOS Medicine.

Acknowledgement: RCWM acknowledge support from the Hong Kong Research Grants Council Research Impact Fund (R4012-18).

Image Credit: stevepb, Pixabay (CC0)

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Charting the evolution of diabetes research and care | Speaking of Medicine - PLoS Blogs