Category Archives: Gene Medicine

A newly discovered immune-system molecule may work against therapies targeting autoimmune disease

By Jenni Laidman

Genetic variations mean that some people have activating Fc receptors on their B cells (red) and are more likely to develop autoimmune diseases. Image: Robert Kimberly, University of Alabama at Birmingham

It was a Reese's Peanut Butter Cup moment in genetic evolution: The end of one gene fused to the beginning of another and, voil, a new, composite gene was born. In most people the two-component gene does not work. But in a small percentage the gene functions and puts its possessors at increased risk for lupus and potentially other autoimmune diseases, in which the immune system attacks the bodys own tissues, says a team of researchers at the University of Alabama at Birmingham.

If the Birmingham researchers are right, the gene could be a clue to improving therapy for autoimmune diseases. At least one prominent researcher has roundly criticized the putative lupus link, however.

In a paper published December 18 in Science Translational Medicine, the Alabama researchers said that working copies of the fused gene disrupt a tidy feedback loop that the immune system uses to regulate the production of antibodiesmolecules that are key players in immune responses to disease-causing microorganisms.

In many autoimmune disorders antibodies run amok, targeting not invading microbes, but a persons organs. Cells known as B lymphocytes, or B cells, secrete the antibodies, and so the B cells make an attractive target for therapies to control autoimmune conditions. Many scientists have focused specifically on manipulating a molecule on B cells that, when bound by antibodies, normally tells the B cells, Stop! No more antibodies! In a healthy immune system, activation of this moleculeknown as Fc gamma RIIb, or the IIb receptor for shortmakes antibody production self-limiting: more antibodies means that more B cells close the antibody tap.

The Alabama team found that, when functional, the Reeses Cup gene causes B cells to manufacture a previously undetected moleculeFc gamma RIIc. When that molecule is activated by an antibody it countermands the IIb stop order, telling B cells to secrete more antibodies. In people with the fusion gene that encodes the IIc receptor molecule, antibodies are just as likely to engage IIc as IIb and thus induce B cells to overproduce antibodies. "We believe this is going to change the way people think about feedback and B cells," Robert Kimberly, co-author of the Science Translational Medicine paper, told Scientific American in a telephone interview.. "The way feedback is depicted in the textbook is incomplete."

The researchers demonstrated the contrarian role of the IIc molecules in studies of both mice and in human and mouse cells in culture. When mice B cells, which don't normally make the IIc molecule, were genetically altered to produce IIc, they generated more antibodies than the B cells of unaltered littermates. Human B cells that had at least one copy of the functioning fusion gene expressed the IIc molecule. Further, the researchers reported, people who carried two copies of the gene that makes IIc had an early immune response to an anthrax vaccine that was two and a half times greater than those without the IIc molecule. Because the vaccine induced antibody production, the rise was another a sign that IIc amps up antibody production. To make the link to IIc and lupus, the researchers compared the genetic profiles of 1,425 people with lupus with the same number without and found that those with the working copies of the IIc-encoding gene had at a 20 percent increased odds of contracting lupusa risk factor the researchers said was equivalent to other established genetic effects for lupus. Up until now, it was assumedgoing back decadesthat there was only a brake on the B cell, Kimberly says. But the expression of IIc counterbalances that brake and gives the B cell a feed-forward signal rather than a feedback.

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New Genetic Clue to Lupus Is Found

Dennis Thompson HealthDay Reporter Posted: Thursday, January 16, 2014, 2:00 PM

THURSDAY, Jan. 16, 2014 (HealthDay News) -- A new gene therapy that successfully treated a rare eye disease in clinical trials could prove the key to preventing more common inherited causes of blindness, researchers say.

In six male patients, doctors used a virus to repair a defective gene that causes choroideremia, a degenerative eye disease that can lead to complete blindness by middle age, according to a clinical trial report published online Jan. 16 in The Lancet.

Vision improved for all the patients following the gene therapy, and particularly for two patients with advanced choroideremia, said lead author Robert MacLaren of the Nuffield Laboratory of Ophthalmology at the University of Oxford, and a consultant surgeon at the Oxford Eye Hospital, in England.

"In truth, we did not expect to see such dramatic improvements in visual acuity and so we contacted both patients' home opticians to get current and historical data on their vision in former years, long before the gene therapy trial started," MacLaren said in a university news release. "These readings confirmed exactly what we had seen in our study and provided an independent verification."

While choroideremia is a rare disease, affecting about one in every 50,000 people, doctors believe the process used to treat it could be turned toward more common inherited eye disorders, such as macular degeneration or retinitis pigmentosa.

"This is something that we've been trying to accomplish for years in retinal science, and it's very encouraging," said Dr. Mark Fromer, an ophthalmologist at Lenox Hill Hospital, in New York City.

Fromer, who was not involved with the new research, predicted that gene therapy could in the future be used to prevent blindness by fixing defective genes in patients before something like macular degeneration can even take root.

"We'll go from putting a Band-Aid on the lesion to preventing it from happening. This is a new pathway to fix things before they get broken," said Fromer, who is also the eye surgeon for the National Hockey League's New York Rangers

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Gene Therapy May Restore Sight in People With Rare Blinding Disease

For patients with choroideremia a rare form of progressive blindness there are no current treatment options that can help stop their visual degeneration. But now a new innovative procedure may be the key.

In a new study published in The Lancet, researchers used a novel gene therapy technique on choroideremia patients, which helped restore some of the sight they had already lost over the years. Gene therapy involves injecting patients with a vital gene that is either missing or defective in their genetic code.

Gene therapy is exciting; its a new type of medicine, lead author Robert MacLaren, a professor at the University of Oxford, told FoxNews.com. And what were doing is it on a very small scale, because were looking at a very straightforward gene to replace.

Caused by a mutation in the CHM gene on the X chromosome, choroideremia causes progressive blindness due to degeneration of the choroid, retinal pigment epithelium and retina. Patients with this disease can start their lives with perfect vision, but eventually start to experience problems with light sensitivity and peripheral vision as they age.

The condition, which affects 1 in every 50,000 people, ultimately leads to the death of the photoreceptor cells in the retina causing complete blindness in middle age.

Its like looking down through a telescope at a small central island of vision, MacLaren explained of the disorder. And by the time theyre in their 40s and 50s, they lose vision completely.

Because choroideremia is caused by a defect in a single gene, MacLaren believed that gene therapy could hold promise for patients with this form of progressive blindness. Additionally, because the cellular degeneration occurs so slowly, the researchers had a large window of opportunity in which they could test their treatment before complete visual loss occurred.

In order to fix the mutation found in choroideremia patients, MacLaren and his colleagues genetically altered an adeno-associated virus (AAV), so that it carried a corrective copy of the CHM gene.

The virus is a small biological organism, and its very good at getting into cells, MacLaren said. But rather than deliver the viruss DNA, weve taken out most of the viral DNA and instead put in the missing gene. So it releases the DNA into the nucleus its a single stranded DNA with the missing [CHM] gene.

The researchers injected their engineered virus into the retinas of six patients between the ages of 35 and 63, all of whom were experiencing different stages of choroideremia. Four of the patients still had good eyesight, though they had almost no peripheral vision, and the other two patients had already started to experience vision loss.

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Gene therapy treats blindness

A gene is a short piece of DNA. Genestells the body how to build a specific proteins. There are about 30,000 genes in each cell of the human body. Together, these genes make up the blueprint for the human body and how it works.

A person's genetic makeup is called a genotype.

Genes are made of DNA. Strands ofDNA strands make up part of your chromosomes. Chromosomes have matching pairs of one copy of a specific gene. The gene occurs in the same position on each chromosome.

Genetic traits, such as eye color, are dominant or recessive:

Many personal characteristics, such as height, are determined by more than one gene. However, some diseases, such as sickle cell anemia, can be caused by a change in a single gene.

Updated by: David C. Dugdale, III, MD, Professor of Medicine, Division of General Medicine, Department of Medicine, University of Washington School of Medicine. Also reviewed by A.D.A.M. Health Solutions, Ebix, Inc., Editorial Team: David Zieve, MD, MHA, David R. Eltz, Stephanie Slon, and Nissi Wang.

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Genes: MedlinePlus Medical Encyclopedia - National Library of ...

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Newswise While the ability of human embryonic stem cells (hESCs) to become any type of mature cell, from neuron to heart to skin and bone, is indisputably crucial to human development, no less important is the mechanism needed to maintain hESCs in their pluripotent state until such change is required.

In a paper published in this weeks Online Early Edition of PNAS, researchers from the University of California, San Diego School of Medicine identify a key gene receptor and signaling pathway essential to doing just that maintaining hESCs in an undifferentiated state.

The finding sheds new light upon the fundamental biology of hESCs with their huge potential as a diverse therapeutic tool but also suggests a new target for attacking cancer stem cells, which likely rely upon the same receptor and pathway to help spur their rampant, unwanted growth.

The research, led by principal investigator Karl Willert, PhD, assistant professor in the Department of Cellular and Molecular Medicine, focuses upon the role of the highly conserved WNT signaling pathway, a large family of genes long recognized as a critical regulator of stem cell self-renewal, and a particular encoded receptor known as frizzled family receptor 7 or FZD7.

WNT signaling through FZD7 is necessary to maintain hESCs in an undifferentiated state, said Willert. If we block FZD7 function, thus interfering with the WNT pathway, hESCs exit their undifferentiated and pluripotent state.

The researchers proved this by using an antibody-like protein that binds to FZD7, hindering its function. Once FZD7 function is blocked with this FZD7-specific compound, hESCs are no longer able to receive the WNT signal essential to maintaining their undifferentiated state.

FZD7 is a so-called onco-fetal protein, expressed only during embryonic development and by certain human tumors. Other studies have suggested that FZD7 may be a marker for cancer stem cells and play an important role in promoting tumor growth. If so, said Willert, disrupting FZD7 function in cancer cells is likely to interfere with their development and growth just as it does in hESCs.

Willert and colleagues, including co-author Dennis Carson, MD, of the Sanford Consortium for Regenerative Medicine and professor emeritus at UC San Diego, plan to further test their FZD7-blocking compound as a potential cancer treatment.

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Keeping Stem Cells Pluripotent

Jan. 14, 2014 The presence of a gene variant in people with mild cognitive impairment (MCI) is associated with accelerated rates of brain atrophy, according to a new study published online in the journal Radiology.

The study focused on the gene apolipoprotein E (APOE), the most important genetic factor known in non-familial Alzheimer's disease (AD). APOE has different alleles, or gene variations, said the study's senior author, Jeffrey R. Petrella, M.D., associate professor of radiology at Duke University School of Medicine in Durham, N.C.

"We all carry two APOE alleles, and most people have at least one copy of the APOE epsilon 3 (3) variant, which is considered neutral with respect to Alzheimer's risk," Dr. Petrella said.

The less common epsilon 4 (4) allele, in contrast, is associated with a higher risk for development of AD, earlier age of onset, and faster progression in those affected, as compared with the other APOE alleles.

Dr. Petrella and colleagues recently analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) involving 237 patients, mean age 79.9, with MCI, a slight but noticeable decline in cognitive ability that is tied to a higher risk of AD. The researchers used MRI to measure brain atrophy rates in these patients over a 12- to 48-month period.

The 4 carriers in the study group exhibited markedly greater atrophy rates than 3 carriers in 13 of 15 brain regions hypothesized to be key components of the cognitive networks disrupted in AD.

"The results showed atrophy in brain regions we know are affected by AD, in a population of patients who do not have AD, but are at risk for it," Dr. Petrella said. "This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially underlies the observed cognitive decline."

The researchers did not explore why APOE 4 might accelerate atrophy, but the affect is likely due to a combination of factors, noted Dr. Petrella.

"The protein has a broad role in the transport and normal metabolism of lipids and a protective function on behalf of brain cells, including its role in the breakdown of beta-amyloid, one of the proteins implicated in the pathophysiology of AD," he said.

With MRI playing an increasingly prominent role in MCI research, Dr. Petrella predicted that increased knowledge about the effects of APOE will improve the design and execution of future clinical trials. For instance, researchers could enrich their samples with 4 patients in MCI prevention trials to better determine potential treatment effects on brain regions vulnerable to degeneration.

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Gene variation associated with brain atrophy in mild cognitive impairment

Oak Brook, Ill. (PRWEB) January 13, 2014

The presence of a gene variant in people with mild cognitive impairment (MCI) is associated with accelerated rates of brain atrophy, according to a new study published online in the journal Radiology.

The study focused on the gene apolipoprotein E (APOE), the most important genetic factor known in non-familial Alzheimers disease (AD). APOE has different alleles, or gene variations, said the studys senior author, Jeffrey R. Petrella, M.D., associate professor of radiology at Duke University School of Medicine in Durham, N.C.

We all carry two APOE alleles, and most people have at least one copy of the APOE epsilon 3 (3) variant, which is considered neutral with respect to Alzheimers risk, Dr. Petrella said.

The less common epsilon 4 (4) allele, in contrast, is associated with a higher risk for development of AD, earlier age of onset, and faster progression in those affected, as compared with the other APOE alleles.

Dr. Petrella and colleagues recently analyzed data from the Alzheimers Disease Neuroimaging Initiative (ADNI) involving 237 patients, mean age 79.9, with MCI, a slight but noticeable decline in cognitive ability that is tied to a higher risk of AD. The researchers used MRI to measure brain atrophy rates in these patients over a 12- to 48-month period.

The 4 carriers in the study group exhibited markedly greater atrophy rates than 3 carriers in 13 of 15 brain regions hypothesized to be key components of the cognitive networks disrupted in AD.

The results showed atrophy in brain regions we know are affected by AD, in a population of patients who do not have AD, but are at risk for it, Dr. Petrella said. This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially underlies the observed cognitive decline.

The researchers did not explore why APOE 4 might accelerate atrophy, but the affect is likely due to a combination of factors, noted Dr. Petrella.

The protein has a broad role in the transport and normal metabolism of lipids and a protective function on behalf of brain cells, including its role in the breakdown of beta-amyloid, one of the proteins implicated in the pathophysiology of AD, he said.

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RSNA: Gene Variation Associated with Brain Atrophy in Mild Cognitive Impairment

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Newswise PHILADELPHIA A new MRI method to map creatine at higher resolutions in the heart may help clinicians and scientists find abnormalities and disorders earlier than traditional diagnostic methods, researchers at the Perelman School of Medicine at the University of Pennsylvania suggest in a new study published online today in Nature Medicine. The preclinical findings show an advantage over less sensitive tests and point to a safer and more cost-effective approach than those with radioactive or contrasting agents.

Creatine is a naturally occurring metabolite that helps supply energy to all cells through creatine kinase reaction, including those involved in contraction of the heart. When heart tissue becomes damaged from a loss of blood supply, even in the very early stages, creatine levels drop. Researchers exploited this process in a large animal model with a method known as CEST, or chemical exchange saturation transfer, which measures specific molecules in the body, to track the creatine on a regional basis.

The team, led by Ravinder Reddy, PhD, professor of Radiology and director of the Center for Magnetic Resonance and Optical Imaging at Penn Medicine, found that imaging creatine through CEST MRI provides higher resolution compared to standard magnetic resonance spectroscopy (MRS), a commonly used technique for measuring creatine. However, its poor resolution makes it difficult to determine exactly which areas of the heart have been compromised.

Measuring creatine with CEST is a promising technique that has the potential to improve clinical decision making while treating patients with heart disorders and even other diseases, as well as spotting problems sooner, said Reddy. Beyond the sensitivity benefits and its advantage over MRS, CEST doesnt require radioactive or contrast agents used in MRI, which can have adverse effects on patients, particularly those with kidney disease, and add to costs.

Today, magnetic resonance imaging (MRI)-based stress tests are also used to identify dead heart tissuewhich is the warning sign of future problems (coronary artery disease, for instance)but its reach is limited. MRI is often coupled with contrast agents to help light up problem areas, but it is often not sensitive enough to find ischemic (but not yet infarcted) regions with deranged metabolism, said Reddy.

After a heart attack, different regions of the heart are damaged at different rates. This new technique will allow us to very precisely study regional changes that occur in the heart after heart attacks, enabling us to identify and treat patients at risk for developing heart failure before symptoms develop, said study co-author Robert C. Gorman, MD, professor of Surgery, and director of Cardiac Surgical Research at Penn Medicine.

To demonstrate CESTs ability to detect heart disease, the researchers applied the creatine CEST method in an MRI scanner, in healthy and infarcted myocardium (muscle tissue in heart) in large animals. In the process, the nuclear magnetization of amine (NH2) creatine protons is saturated by a radiofrequency pulse from the MRI. After the exchange with water, the degree of saturation is observed as the water signal drops, and thus the concentration of creatine becomes apparent. (In the body, creatine is converted to creatinine, which can be measured through blood and urine tests and is an important tool for assessing renal function.)

The team showed that the creatine CEST method can map changes in creatine levels, and pinpoint infarcted areas in heart muscle tissue, just as MRS methods can. However, they found, CEST has two orders of magnitude higher sensitivity than MRS. That advantage could help spot smaller damaged areas in the heart missed by traditional methods, the authors say.

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Tweaking MRI to Track Creatine May Spot Heart Problems Earlier, Penn Medicine Study Suggests

Jan. 9, 2014 A new study is giving researchers hope that novel targeted therapies can be developed for glioblastoma multiforme (GBM), the most common and most aggressive form of brain cancer, after demonstrating for the first time that a gene known as melanoma differentiation associated gene-9/syntenin (mda-9/syntenin) is a driving force behind the disease's aggressive and invasive nature.

Recently published in the journal Neuro-Oncology, the study led by Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) researchers used cell cultures and animal models to uncover the mechanisms by which mda-9/syntenin causes GBM to grow and invade normal brain tissue. Additionally, by using publicly available cancer genomic database information (bioinformatics) and analyzing tissue samples from patients with GBM, the researchers found that increased levels of mda-9/syntenin correlated with more advanced tumors and shorter survival. The study's discoveries pinpoint molecular targets that could be used to develop new therapies, and also suggest that the gene could be used to help stage and monitor this aggressive disease.

"Our current study represents a major breakthrough in understanding what drives GBM, and it is a starting point for the development of future therapies," says the study's lead author Paul B. Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. "Because mda-9/syntenin is expressed more in advanced disease, we are also hopeful that we may be able to use the gene to monitor for disease progression and test whether certain therapies are working."

Mda-9/syntenin was originally discovered by Fisher, and through bioinformatics he has found that the gene is overexpressed in a majority of cancers. He and his colleagues also found that mda-9/syntenin interacts with a predicted 151 cancer-related proteins through its PDZ domains, which are chains of amino acids that enable cell signaling by facilitating interactions between proteins.

In GBM, Fisher and his colleagues demonstrated that overexpression of mda-9/syntenin enhanced the cells' ability to invade healthy tissue. In contrast, blocking expression of mda-9/syntenin in animal models reduced invasion, suppressed cell migration and caused tumors to shrink. Additionally, blocking the expression of mda-9/syntenin decreased the production and secretion of interleukin 8 (IL-8) proteins, which are signaling proteins that contribute to tumor growth and progression by promoting cell migration and the development of new blood vessels, a process known as angiogenesis.

"We are now focusing on developing small molecules, or drugs, that block the binding of specific cancer-promoting proteins that interact with mda-9/syntenin through its PDZ domains," says Fisher. "If successful, these PDZ-targeted therapies could potentially lead to effective treatments for GBM."

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Scientists uncover new target for brain cancer treatment

New York, Jan 9:

Scientists have identified 14 new genes potentially implicated in Alzheimers disease.

One gene in particular demonstrates the important role inflammation may play in the brain of Alzheimers patients, researchers who successfully generated a stem cell model of familial Alzheimers disease (FAD), said.

A team of scientists at The New York Stem Cell Foundation (NYSCF) Research Institute and the Icahn School of Medicine at Mount Sinai (ISMMS) produced stem cells and neural precursor cells (NPCs), representing early neural progenitor cells that build the brain from patients with severe early-onset AD with mutations in the Presenilin 1 (PSEN1) gene.

These NPCs had elevated Abeta42/Abeta40 ratios, indicating elevation of the form of amyloid found in the brains of Alzheimers patients.

These levels were greater than those in adult cells that did not have the PSEN1 mutation. This elevated ratio shows that the NPCs grown in the petri dish accurately reflected the cells in the brains of FAD patients.

The gene expression profile from the familial Alzheimers stem cells points to inflammation, which is especially exciting because we would not usually associate inflammation with this particular Alzheimers gene, said Sam Gandy, co-author on the study.

The researchers generated induced pluripotent stem (iPS) cells from affected and unaffected individuals from two families carrying PSEN1 mutations.

After thorough characterisation of the NPCs through gene expression profiling and other methods, they identified 14 genes that behaved differently in PSEN1 NPCs relative to NPCs from individuals without the mutation. Five of these targets also showed differential expression in late onset Alzheimers disease patients brains.

Therefore, in the PSEN1 iPS cell model, the researchers reconstituted an essential feature in the molecular development of familial Alzheimers disease. The study was published in the journal PLOS ONE.

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14 new gene targets in Alzheimer’s identified