Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

20-Nov-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-5232 University of California - San Diego @UCSanDiego

While investigating a rare genetic disorder, researchers at the University of California, San Diego School of Medicine have discovered that a ubiquitous signaling molecule is crucial to cellular reprogramming, a finding with significant implications for stem cell-based regenerative medicine, wound repair therapies and potential cancer treatments.

The findings are published in the Nov. 20 online issue of Cell Reports.

Karl Willert, PhD, assistant professor in the Department of Cellular and Molecular Medicine, and colleagues were attempting to use induced pluripotent stem cells (iPSC) to create a "disease-in-a-dish" model for focal dermal hypoplasia (FDH), a rare inherited disorder caused by mutations in a gene called PORCN. Study co-authors V. Reid Sutton and Ignatia Van den Veyver at Baylor College of Medicine had published the observation that PORCN mutations underlie FDH in humans in 2007.

FDH is characterized by skin abnormalities such as streaks of very thin skin or different shades, clusters of visible veins and wartlike growths. Many individuals with FDH also suffer from hand and foot abnormalities and distinct facial features. The condition is also known as Goltz syndrome after Robert Goltz, who first described it in the 1960s. Goltz spent the last portion of his career as a professor at UC San Diego School of Medicine. He retired in 2004 and passed away earlier this year.

To their surprise, Willert and colleagues discovered that attempts to reprogram FDH fibroblasts or skin cells with the requisite PORCN mutation into iPSCs failed using standard methods, but succeeded when they added WNT proteins - a family of highly conserved signaling molecules that regulate cell-to-cell interactions during embryogenesis.

"WNT signaling is ubiquitous," said Willert. "Every cell expresses one or more WNT genes and every cell is able to receive WNT signals. Individual cells in a dish can grow and divide without WNT, but in an organism, WNT is critical for cell-cell communication so that cells distinguish themselves from neighbors and thus generate distinct tissues, organs and body parts."

WNT signaling is also critical in limb regeneration (in some organisms) and tissue repair.

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Signaling molecule crucial to stem cell reprogramming

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Newswise UCLA stem cell researchers have pioneered a stem cell gene therapy cure for children born with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), often called Bubble Baby disease, a life-threatening condition that if left untreated can be fatal within the first year of life.

The groundbreaking treatment was developed by renowned stem cell researcher and UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. Donald Kohn, whose breakthrough was developed over three decades of research to create a gene therapy that safely restores immune systems in children with ADA-deficient SCID using the patients own cells with no side effects.

To date, 18 children with SCID have been cured of the disease after receiving the stem cell gene therapy in clinical trials at UCLA and the National Institutes of Health.

All of the children with SCID that I have treated in these stem cell clinical trials would have died in a year or less without this gene therapy, instead they are all thriving with fully functioning immune systems said Kohn, a professor of pediatrics and of microbiology, immunology and molecular genetics in Life Sciences.

To protect children born with SCID they are kept in isolation, in controlled environments because without an immune system they are extremely vulnerable to illness and infection that could be lethal.

Other current options for treating ADA-deficient SCID are not always optimal or feasible for many children, said Kohn. We can now, for the first time, offer these children and their families a cure, and the chance to live a full healthy life.

Defeating ADA-Deficient SCID: A Game-Changing Approach

Children born with SCID, an inherited immunodeficiency, are generally diagnosed at about six months. They are extremely vulnerable to infectious diseases, and in a child with ADA-deficient SCID even the common cold can prove fatal. The disease causes cells to not create an enzyme called ADA, which is critical for production of the healthy white blood cells that drive a normal, fully-functioning immune system. About 15 percent of all SCID patients are ADA-deficient.

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UCLA Stem Cell Researcher Pioneers Gene Therapy Cure for Children with "Bubble Baby" Disease

Researchers at the University of Cincinnati (UC) have found that a gene abundant in the kidneys may actually play a role in the regulation of blood pressure and hypertension in experimental male mouse models.

The study led by Manoocher Soleimani, MD, James F. Heady Professor of Medicine and associate chair of research in the Department of Internal Medicine at UC, was presented during the annual meeting of the American Society of Nephrology, held Friday, Nov. 15, 2014, in Philadelphia.

The gene, a kidney androgen-regulated protein (KAP) that is abundantly and exclusively found in the kidney proximal tubule, is stimulated by an androgen hormone such as testosterone, says Soleimani.

The function of KAP in the kidney remains unknown, but in an attempt to investigate the gene's role, researchers studied mice developed with a deficiency of the KAP gene. Those mice were compared to a control group of mice.

"The male KAP deficient mice displayed significantly reduced blood pressure," says Soleimani. "Placing the animals on a high salt diet for 14 days led to normalization of blood pressure in the male KAP deficient mice without significantly affecting the control group. These results have significant ramifications."

Soleimani said the results may be helpful in understanding ways to control high blood pressure in humans, specifically in men. About 67 million Americans -- or one in every three adults -- have high blood pressure, according to the Centers for Disease Control and Prevention.

"It is well known that men are more prone to develop hypertension than women, specifically before the age of 50," says Soleimani. "While this has correlated with higher testosterone levels in men, the exact association between male hormones and hypertension remains unknown. Our results suggests that KAP, which is regulated by testosterone plays an important role in systemic blood pressure in male animals through regulation of salt absorption in the kidney tubule."

"Our findings also nicely explain the historical observations which have demonstrated male sex hormones contribute to the worsening of hypertension."

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The above story is based on materials provided by University of Cincinnati Academic Health Center. Note: Materials may be edited for content and length.

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Gene found in kidney may play role in high blood pressure in male mice

Using next generation gene sequencing techniques, cancer researchers at UT Southwestern Medical Center have identified more than 3,000 new mutations involved in certain kidney cancers, findings that help explain the diversity of cancer behaviors.

"These studies, which were performed in collaboration with Genentech Inc., identify novel therapeutic targets and suggest that predisposition to kidney cancer across species may be explained, at least in part, by the location of tumor suppressor genes with respect to one another in the genome," said Dr. James Brugarolas, Associate Professor of Internal Medicine and Developmental Biology, who leads UT Southwestern's Kidney Cancer Program at the Harold C. Simmons Cancer Center.

The scientists' findings are outlined in separate reports in the Proceedings of the National Academy of Sciences and Nature Genetics.

More than 250,000 individuals worldwide are diagnosed with kidney cancer every year, with lifetime risk of kidney cancer in the US estimated at 1.6 percent. Most kidney tumors are renal cell carcinomas, which when metastatic remain largely incurable.

Researchers with UT Southwestern's Kidney Cancer Program had previously identified a critical gene called BAP1 that is intimately tied to kidney cancer formation. Their latest research shows how BAP1 interacts with a second gene, VHL, to transform a normal kidney cell into a cancer cell, which in part appears to be based on the two gene's close proximity in humans, said Dr. Brugarolas, a Virginia Murchison Linthicum Endowed Scholar in Medical Research.

The newest findings suggest that the transformation begins with a mutation in one of the two copies of VHL, which is the most frequently mutated gene in the most common form of kidney cancer, clear cell type, which accounts for about 75 percent of kidney cancers. The VHL mutation is followed by a loss of the corresponding chromosome arm containing the second copy of VHL, as well as several other genes including PBRM1 and BAP1. This step eliminates the remaining copy of VHL and along with it, one of the two copies of PBRM1 and BAP1, two important genes that protect the kidney from cancer development. The subsequent mutation of the remaining copy of BAP1 leads to aggressive tumors, whereas mutation of the remaining copy of PBRM1 induces less aggressive tumors, said Dr. Payal Kapur, a key investigator of both studies who is an Associate Professor of Pathology and Urology, and the Pathology co-Leader of the Kidney Cancer Program.

This model also explains why humans born with a mutation in VHL have a high likelihood of developing kidney cancer during their life time. In these individuals, all kidney cells are already deficient for one VHL copy and a single deletion eliminates the second copy, along with a copy of BAP1 and PBRM1. In contrast, in other animals, these three genes are located on different chromosomes and thus more mutational events are required for their inactivation than in humans. Consistent with this notion, when UT Southwestern researchers mutated VHL and BAP1 together, kidney cancer resulted in animals.

In a second collaborative study with Genentech Inc., published in Nature Genetics, investigators implicated several genes for the first time in non-clear cell kidney cancer, a less common type that accounts for about 25 percent of kidney cancers. Researchers identified a gene signature that can help differentiate subtypes of non-clear cell tumors to better define their behavior. Specifically, the researchers characterized alterations from 167 human primary non-clear cell renal cell carcinomas, identifying 16 significantly mutated genes in non-clear cell kidney cancer that may pave the way for the development of novel therapies. The research team also identified a five-gene set that enabled molecular classifications of tumor subtypes, along with a potential therapeutic role for BIRC7 inhibitors for future study.

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The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.

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Gene Mutations and Process for How Kidney Tumors Develop identified

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Newswise DALLAS November 17, 2014 Using next generation gene sequencing techniques, cancer researchers at UT Southwestern Medical Center have identified more than 3,000 new mutations involved in certain kidney cancers, findings that help explain the diversity of cancer behaviors.

These studies, which were performed in collaboration with Genentech Inc., identify novel therapeutic targets and suggest that predisposition to kidney cancer across species may be explained, at least in part, by the location of tumor suppressor genes with respect to one another in the genome, said Dr. James Brugarolas, Associate Professor of Internal Medicine and Developmental Biology, who leads UT Southwesterns Kidney Cancer Program at the Harold C. Simmons Cancer Center.

The scientists findings are outlined in separate reports in the Proceedings of the National Academy of Sciences and Nature Genetics.

More than 250,000 individuals worldwide are diagnosed with kidney cancer every year, with lifetime risk of kidney cancer in the US estimated at 1.6 percent. Most kidney tumors are renal cell carcinomas, which when metastatic remain largely incurable.

Researchers with UT Southwesterns Kidney Cancer Program had previously identified a critical gene called BAP1 that is intimately tied to kidney cancer formation. Their latest research shows how BAP1 interacts with a second gene, VHL, to transform a normal kidney cell into a cancer cell, which in part appears to be based on the two genes close proximity in humans, said Dr. Brugarolas, a Virginia Murchison Linthicum Endowed Scholar in Medical Research.

The newest findings suggest that the transformation begins with a mutation in one of the two copies of VHL, which is the most frequently mutated gene in the most common form of kidney cancer, clear cell type, which accounts for about 75 percent of kidney cancers. The VHL mutation is followed by a loss of the corresponding chromosome arm containing the second copy of VHL, as well as several other genes including PBRM1 and BAP1. This step eliminates the remaining copy of VHL and along with it, one of the two copies of PBRM1 and BAP1, two important genes that protect the kidney from cancer development. The subsequent mutation of the remaining copy of BAP1 leads to aggressive tumors, whereas mutation of the remaining copy of PBRM1 induces less aggressive tumors, said Dr. Payal Kapur, a key investigator of both studies who is an Associate Professor of Pathology and Urology, and the Pathology co-Leader of the Kidney Cancer Program.

This model also explains why humans born with a mutation in VHL have a high likelihood of developing kidney cancer during their life time. In these individuals, all kidney cells are already deficient for one VHL copy and a single deletion eliminates the second copy, along with a copy of BAP1 and PBRM1. In contrast, in other animals, these three genes are located on different chromosomes and thus more mutational events are required for their inactivation than in humans. Consistent with this notion, when UT Southwestern researchers mutated VHL and BAP1 together, kidney cancer resulted in animals.

In a second collaborative study with Genentech Inc., published in Nature Genetics, investigators implicated several genes for the first time in non-clear cell kidney cancer, a less common type that accounts for about 25 percent of kidney cancers. Researchers identified a gene signature that can help differentiate subtypes of non-clear cell tumors to better define their behavior. Specifically, the researchers characterized alterations from 167 human primary non-clear cell renal cell carcinomas, identifying 16 significantly mutated genes in non-clear cell kidney cancer that may pave the way for the development of novel therapies. The research team also identified a five-gene set that enabled molecular classifications of tumor subtypes, along with a potential therapeutic role for BIRC7 inhibitors for future study.

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Researchers Identify Gene Mutations and Process for How Kidney Tumors Develop

PUBLIC RELEASE DATE:

17-Nov-2014

Contact: Cedric Ricks cedric.ricks@uc.edu 513-558-4657 University of Cincinnati Academic Health Center @UCHealthNews

CINCINNATI--Researchers at the University of Cincinnati (UC) have found that a gene abundant in the kidneys may actually play a role in the regulation of blood pressure and hypertension in experimental male mouse models.

The study led by Manoocher Soleimani, MD, James F. Heady Professor of Medicine and associate chair of research in the Department of Internal Medicine at UC, was presented during the annual meeting of the American Society of Nephrology, held Friday, Nov. 15, 2014, in Philadelphia.

The gene, a kidney androgen-regulated protein (KAP) that is abundantly and exclusively found in the kidney proximal tubule, is stimulated by an androgen hormone such as testosterone, says Soleimani.

The function of KAP in the kidney remains unknown, but in an attempt to investigate the gene's role, researchers studied mice developed with a deficiency of the KAP gene. Those mice were compared to a control group of mice.

"The male KAP deficient mice displayed significantly reduced blood pressure," says Soleimani. "Placing the animals on a high salt diet for 14 days led to normalization of blood pressure in the male KAP deficient mice without significantly affecting the control group. These results have significant ramifications."

Soleimani said the results may be helpful in understanding ways to control high blood pressure in humans, specifically in men. About 67 million Americans--or one in every three adults--have high blood pressure, according to the Centers for Disease Control and Prevention.

"It is well known that men are more prone to develop hypertension than women, specifically before the age of 50," says Soleimani. "While this has correlated with higher testosterone levels in men, the exact association between male hormones and hypertension remains unknown. Our results suggests that KAP, which is regulated by testosterone plays an important role in systemic blood pressure in male animals through regulation of salt absorption in the kidney tubule."

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Researchers find gene in kidney may play role in high blood pressure in male mice

Latest Infectious Disease News

THURSDAY, Nov. 13, 2014 (HealthDay News) -- It may be possible to identify different types of hemorrhagic fevers -- including one related to Ebola -- before people develop symptoms, according to new research.

Scientists studied two hemorrhagic fevers, including a cousin of Ebola called Marburg and another called Lassa. Marburg causes occasional outbreaks in Africa that have high death rates, and Lassa is common is Western Africa, the researchers reported.

Using genetic material from white blood cells, researchers from the Boston University School of Medicine and the U.S. Army Medical Research Institute were able to recognize changes in the way the genes behaved in the early stages of infection. These changes occur before someone would even have symptoms, according to the researchers. They also occur before the infection could be passed to others, according to the study published recently in the journal BMC Genomics.

The findings could help lead to better ways to diagnose hemorrhagic fevers during the early stages, when treatments and containment efforts are more likely to be effective, the researchers suggested.

They noted that early indications of hemorrhagic fevers (fever, flu symptoms) are similar, which makes proper diagnosis difficult. More disease-specific symptoms and the ability to spread the virus from person to person don't begin until after the virus has accumulated in the blood.

"The ability to distinguish between different types of infection before the appearance of overt clinical symptoms has important implications for guiding triage and containment during epidemics," study corresponding author Nacho Caballero, a Ph.D. candidate at Boston University School of Medicine, said in a university news release.

"We hope that our study will help in the development of better diagnostics, especially during the early stages of disease, when treatments have a greater chance of being effective," he added.

However, Caballero noted that "this is not a finding that can be translated into a test tomorrow. This study supports the idea that early markers of infection are there, but significant work will still need to be done to extend these findings."

-- Robert Preidt

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Gene Analysis May Help Spot Ebola-Like Illnesses Before Symptoms Appear

PUBLIC RELEASE DATE:

12-Nov-2014

Contact: Julia Evangelou Strait straitj@wustl.edu 314-286-0141 Washington University School of Medicine @WUSTLmed

Rare mutations that shut down a single gene are linked to lower cholesterol levels and a 50 percent reduction in the risk of heart attack, according to new research from Washington University School of Medicine in St. Louis, the Broad Institute at Massachusetts Institute of Technology and Harvard, and other institutions.

The gene, called NPC1L1, is of interest because it is the target of the drug ezetimibe, often prescribed to lower cholesterol.

The study appears Nov. 12 in The New England Journal of Medicine.

Everyone inherits two copies of most genes -- one copy from each parent. In the study, the researchers found that people with one inactive copy of NPC1L1 appeared to be protected against high LDL cholesterol --the so-called "bad" cholesterol -- and coronary heart disease, a narrowing of the heart's arteries that can lead to heart attacks.

"This analysis demonstrates that human genetics can guide us in terms of thinking about appropriate genes to target for clinical therapy," said first author Nathan O. Stitziel, MD, PhD, a cardiologist at Washington University School of Medicine. "When people have one copy of a gene not working, it's a little like taking a drug their entire lives that is inhibiting this gene."

The investigators mined genetic data from large clinical trials to find individuals with naturally occurring mutations in the NPC1L1 gene that completely shut it down. They analyzed multiple existing studies, pooling data from about 113,000 people. Of these trial participants, only 82 were found to have a mutation that shut off one copy of the NPC1L1 gene. No one had two inactive copies of NPC1L1. Based on a subset of data in the analysis, the researchers estimate roughly 1 in 650 people carry one inactive version of the gene.

The investigators found that people with only one working copy of the gene had LDL cholesterol levels an average of 12 milligrams per deciliter lower than the wider population of people with two working copies of the gene. This approximately 10 percent reduction in LDL cholesterol is comparable to that seen in patients taking ezetimibe. But beyond simply lowering cholesterol, the 82 people with inactive copies also had about half the risk of coronary heart disease as people with two functional copies of the gene.

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Errors in single gene may protect against heart disease

PUBLIC RELEASE DATE:

13-Nov-2014

Contact: Matt Solovey msolovey@hmc.psu.edu 717-531-8606 Penn State @penn_state

Mice bred to carry a gene variant found in a third of ALS patients have a faster disease progression and die sooner than mice with the standard genetic model of the disease, according to Penn State College of Medicine researchers. Understanding the molecular pathway of this accelerated model could lead to more successful drug trials for all ALS patients.

Amyotrophic lateral sclerosis, commonly known as Lou Gehrig's disease, is a degeneration of lower and upper motor neurons in the brainstem, spinal cord and the motor cortex. The disease, which affects 12,000 Americans, leads to loss of muscle control. People with ALS typically die of respiratory failure when the muscles that control breathing fail.

Penn State researchers were the first to discover increased iron levels in the brains of some patients with the late-onset neurodegenerative disorders Parkinson's disease and Alzheimer's disease. A decade ago, they also identified a relationship between ALS and excess iron accumulation when they found that 30 percent of ALS patients in their clinic carried a variant of a gene known as HFE that is associated with iron overload disease.

For this study, the researchers crossbred mice with the HFE gene variant with the standard mice used in ALS research.

"When we followed the disease progression and the behavior of our crossbred mice compared to the standard mice, we saw significant differences," said James Connor, vice chair of neurosurgery research and director of the Center for Aging and Neurodegenerative Diseases. The crossbred mice performed significantly worse on tests of forelimb and hindlimb grip strength and had a 4 percent shorter life span. The researchers published their findings in BBA Molecular Basis of Disease.

"The disease progression was much faster in the crossbred mice than in the standard mice," Connor said. "What we found is that when ALS happens in the presence of the HFE gene variant, things go downhill more quickly."

The lead investigator on this project, graduate student Wint Nandar, noticed that the HFE gene variant sped up disease progression and death in females but not males. Males with ALS die faster, on average, than females.

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Genotype found in 30 percent of ALS patients speeds up disease progression

Published November 13, 2014

Scientists have discovered gene mutations that give people naturally lower cholesterol levels and cut their risk of heart disease in half.

That discovery may have a big implication: A blockbuster drug that mimics these mutations has long been sold without evidence that it cuts the chance of heart disease. Results of a large study that looked for that evidence will be revealed on Monday.

The drug is Merck & Co.'s Zetia, also sold in combination with another medicine as Vytorin.

When Zetia was designed, scientists knew how it worked to lower LDL, or bad cholesterol, and it won federal approval based on its ability to do that. But the existence of gene mutations that could do the same thing was not known, nor was it known if lowering cholesterol this way would translate to a lower risk of heart problems.

The new research gives a biological basis to suggest the drug could help.

Researchers found that people with mutations in a gene called NPC1L1 had LDL that was 12 milligrams per deciliter lower on average than others without a mutation. That is similar to how much Zetia lowers LDL.

The bigger finding was that the gene mutations lowered the risk of heart disease by 53 percent.

"It's a stunner," said Dr. Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California. "We're learning more and more about protective mutations," and the effect these had on heart disease risk was far greater than the degree to which they lowered cholesterol, he said.

Topol had no role in the study, which was led by researchers from the Washington University School of Medicine in St. Louis, the Broad Institute at the Massachusetts Institute of Technology and Harvard, and other institutions. Results were published online Wednesday by the New England Journal of Medicine.

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Gene mutation discovery boosts interest in heart drug