The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.

The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.

Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.

The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.

On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.

On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.

Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.

Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.

Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.

[email protected]

The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.

The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.

Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.

The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.

On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.

On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.

Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.

Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.

Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.

[email protected]

The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.

The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.

Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.

The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.

On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.

On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.

Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.

Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.

Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.

[email protected]

GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.

Will Pass/MDedge News

This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.

At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.

The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.

Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.

Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.

Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”

Will Pass/MDedge News

“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.

“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.

The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.

SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.

GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.

Will Pass/MDedge News

This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.

At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.

The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.

Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.

Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.

Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”

Will Pass/MDedge News

“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.

“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.

The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.

SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.

GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.

Will Pass/MDedge News

This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.

At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.

The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.

Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.

Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.

Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”

Will Pass/MDedge News

“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.

“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.

The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.

SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.

SAN FRANCISCO – New York University researchers have found a ninefold increase of the bacterium Ruminococcus gnavus in the intestines of particularly ill lupus patients.

Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.

That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.

R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.

“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.

“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.

“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.

Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.

SAN FRANCISCO – New York University researchers have found a ninefold increase of the bacterium Ruminococcus gnavus in the intestines of particularly ill lupus patients.

Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.

That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.

R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.

“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.

“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.

“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.

Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.

SAN FRANCISCO – New York University researchers have found a ninefold increase of the bacterium Ruminococcus gnavus in the intestines of particularly ill lupus patients.

Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.

That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.

R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.

“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.

“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.

“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.

Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.

ORLANDO – Stem cell models could boost schizophrenia treatment to a new level, helping to gauge the importance of both rare and common genetic variants that are difficult to study in traditional-style trials, an expert said at the annual congress of the Schizophrenia International Research Society.

The promise of the approach is particularly crucial at this point in the course of schizophrenia research, when the heritability of the disease is being repeatedly underscored in the literature, said Kristen Brennand, PhD, associate professor of neuroscience, genetics and genomics, and psychiatry at the Icahn School of Medicine at Mount Sinai, New York.

“It seems that each new paper that comes out raises that estimate of heritability and the numbers I’ve seen recently are as high as 85%,” she said. “Schizophrenia is as heritable as autism and bipolar, more heritable than BRCA1 breast cancer, it’s more heritable than alcoholism. But that heritability is highly complex.”

Highly penetrant variants that are more easily studied account for only a small sliver of this heritability. Rare variants that are harder to study account for more. And common variants – the count is up to 145 and will almost certainly grow – also play a big role.

“These are variants that all of us carry,” Dr. Brennand said. “We all carry dozens of these variants. Patients just either carry more of them or they’re hitting pathways in a different way than they’re hitting the rest of us.”

Using human-induced pluripotent stem cells (HiPSC) – grown out of skin biopsy samples from schizophrenia patients and then grown into neural progenitor cells and ultimately neurons – are much more practical for studying the genetics of these variants than case-control studies that require tens of thousands of subjects.

Researchers have found that cohorts using HiPSCs concord with the genetic findings from postmortem datasets of schizophrenia patients.

More recently, in work not yet published, she said her lab has focused on rare 2p16.3 deletions of the NRXN1 gene, finding that neuronal branching is reduced and that there is decreased neuronal activity in schizophrenia patients with these deletions.

Her lab is also using HiPSCs and clustered regularly interspaced short palindromic repeats editing to validate the function of common variants and genes linked with schizophrenia. A key finding has been that there could be important relationships between risk genes that are more distant from schizophrenia single-nucleotide polymorphisms (SNPs).

“We’re expanding the list of potential schizophrenia risk genes by considering not just immediately proximal but also distal interactions between schizophrenia SNPs,” Dr. Brennand said. “If there are 224 genes that are next to risk SNPs, you can add a few hundred more potential genes that might be coregulated by these risk SNPs.”

Harnessing the power of HiPSCs could be the gateway to precision medicine in schizophrenia, she said. A drug that might benefit, say, two out of a dozen patients would likely fail in a clinical trial, unless patient selection is improved.

“Perhaps genotype might predict clinical response, perhaps stem cell drug responsiveness might predict clinical response,” she said. “What I envision is this dream where we have patients and we genotype them, and we better understand how their DNA impacts their gene expression, and how their gene expression impacts their synaptic function, and that this might help us better understand their prognosis.”

Dr. Brennand reported a financial relationship with Alkermes.

ORLANDO – Stem cell models could boost schizophrenia treatment to a new level, helping to gauge the importance of both rare and common genetic variants that are difficult to study in traditional-style trials, an expert said at the annual congress of the Schizophrenia International Research Society.

The promise of the approach is particularly crucial at this point in the course of schizophrenia research, when the heritability of the disease is being repeatedly underscored in the literature, said Kristen Brennand, PhD, associate professor of neuroscience, genetics and genomics, and psychiatry at the Icahn School of Medicine at Mount Sinai, New York.

“It seems that each new paper that comes out raises that estimate of heritability and the numbers I’ve seen recently are as high as 85%,” she said. “Schizophrenia is as heritable as autism and bipolar, more heritable than BRCA1 breast cancer, it’s more heritable than alcoholism. But that heritability is highly complex.”

Highly penetrant variants that are more easily studied account for only a small sliver of this heritability. Rare variants that are harder to study account for more. And common variants – the count is up to 145 and will almost certainly grow – also play a big role.

“These are variants that all of us carry,” Dr. Brennand said. “We all carry dozens of these variants. Patients just either carry more of them or they’re hitting pathways in a different way than they’re hitting the rest of us.”

Using human-induced pluripotent stem cells (HiPSC) – grown out of skin biopsy samples from schizophrenia patients and then grown into neural progenitor cells and ultimately neurons – are much more practical for studying the genetics of these variants than case-control studies that require tens of thousands of subjects.

Researchers have found that cohorts using HiPSCs concord with the genetic findings from postmortem datasets of schizophrenia patients.

More recently, in work not yet published, she said her lab has focused on rare 2p16.3 deletions of the NRXN1 gene, finding that neuronal branching is reduced and that there is decreased neuronal activity in schizophrenia patients with these deletions.

Her lab is also using HiPSCs and clustered regularly interspaced short palindromic repeats editing to validate the function of common variants and genes linked with schizophrenia. A key finding has been that there could be important relationships between risk genes that are more distant from schizophrenia single-nucleotide polymorphisms (SNPs).

“We’re expanding the list of potential schizophrenia risk genes by considering not just immediately proximal but also distal interactions between schizophrenia SNPs,” Dr. Brennand said. “If there are 224 genes that are next to risk SNPs, you can add a few hundred more potential genes that might be coregulated by these risk SNPs.”

Harnessing the power of HiPSCs could be the gateway to precision medicine in schizophrenia, she said. A drug that might benefit, say, two out of a dozen patients would likely fail in a clinical trial, unless patient selection is improved.

“Perhaps genotype might predict clinical response, perhaps stem cell drug responsiveness might predict clinical response,” she said. “What I envision is this dream where we have patients and we genotype them, and we better understand how their DNA impacts their gene expression, and how their gene expression impacts their synaptic function, and that this might help us better understand their prognosis.”

Dr. Brennand reported a financial relationship with Alkermes.

ORLANDO – Stem cell models could boost schizophrenia treatment to a new level, helping to gauge the importance of both rare and common genetic variants that are difficult to study in traditional-style trials, an expert said at the annual congress of the Schizophrenia International Research Society.

The promise of the approach is particularly crucial at this point in the course of schizophrenia research, when the heritability of the disease is being repeatedly underscored in the literature, said Kristen Brennand, PhD, associate professor of neuroscience, genetics and genomics, and psychiatry at the Icahn School of Medicine at Mount Sinai, New York.

“It seems that each new paper that comes out raises that estimate of heritability and the numbers I’ve seen recently are as high as 85%,” she said. “Schizophrenia is as heritable as autism and bipolar, more heritable than BRCA1 breast cancer, it’s more heritable than alcoholism. But that heritability is highly complex.”

Highly penetrant variants that are more easily studied account for only a small sliver of this heritability. Rare variants that are harder to study account for more. And common variants – the count is up to 145 and will almost certainly grow – also play a big role.

“These are variants that all of us carry,” Dr. Brennand said. “We all carry dozens of these variants. Patients just either carry more of them or they’re hitting pathways in a different way than they’re hitting the rest of us.”

Using human-induced pluripotent stem cells (HiPSC) – grown out of skin biopsy samples from schizophrenia patients and then grown into neural progenitor cells and ultimately neurons – are much more practical for studying the genetics of these variants than case-control studies that require tens of thousands of subjects.

Researchers have found that cohorts using HiPSCs concord with the genetic findings from postmortem datasets of schizophrenia patients.

More recently, in work not yet published, she said her lab has focused on rare 2p16.3 deletions of the NRXN1 gene, finding that neuronal branching is reduced and that there is decreased neuronal activity in schizophrenia patients with these deletions.

Her lab is also using HiPSCs and clustered regularly interspaced short palindromic repeats editing to validate the function of common variants and genes linked with schizophrenia. A key finding has been that there could be important relationships between risk genes that are more distant from schizophrenia single-nucleotide polymorphisms (SNPs).

“We’re expanding the list of potential schizophrenia risk genes by considering not just immediately proximal but also distal interactions between schizophrenia SNPs,” Dr. Brennand said. “If there are 224 genes that are next to risk SNPs, you can add a few hundred more potential genes that might be coregulated by these risk SNPs.”

Harnessing the power of HiPSCs could be the gateway to precision medicine in schizophrenia, she said. A drug that might benefit, say, two out of a dozen patients would likely fail in a clinical trial, unless patient selection is improved.

“Perhaps genotype might predict clinical response, perhaps stem cell drug responsiveness might predict clinical response,” she said. “What I envision is this dream where we have patients and we genotype them, and we better understand how their DNA impacts their gene expression, and how their gene expression impacts their synaptic function, and that this might help us better understand their prognosis.”

Dr. Brennand reported a financial relationship with Alkermes.