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Newswise Researchers at the University of California, San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimers disease (AD). The study, published March 12 in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.

Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons, said senior author Lawrence Goldstein, PhD, director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program. This is potentially significant for slowing the progression of Alzheimers disease. AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.

The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.

Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.

The studys primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.

For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.

The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.

BDNF is found in everyones brain, said first author Jessica Young, PhD, a postdoctoral fellow in the Goldstein laboratory. What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons dont respond. Those with the protective genetic profile do.

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Boosting A Natural Protection Against Alzheimer's Disease

Researchers at the University of Bonn discover a new hereditary factor associated with a rare disease

IMAGE:This image shows Prof. Dr. Michael Ludwig, Dr. Heiko Reutter and Prof. Dr. Markus Nthen of the University of Bonn Hospital (from left). view more

Credit: (c) Photo: Katharina Wislsperger/UKB

An interdisciplinary team of researchers under the direction of the University of Bonn Hospital have discovered a gene which is associated with a rare congenital anomaly of the urinary tract called classic bladder exstrophy. It increases the likelihood that the urinary tract will not form properly during embryonic development. The finding is an important step for understanding the development of urinary tract malformations in general and for developing prophylactic measures. The results are published in the current online edition of the journal "PloS Genetics".

The kidneys and urinary tract are the sites affected most frequently by congenital malformations. Approximately 1 out of every 200 children suffers from such a malformation. "These diseases make up about 20 to 30 percent of all congenital malformations," says Associate Professor Dr. Heiko Reutter from the Institute of Human Genetics and the Department of Neonatology and Pediatric Intensive Care Medicine of the University of Bonn.

For many years, the pediatrician has investigated the genetic causes of classic bladder exstrophy comprising malformations ranging from the bladder to the entire urinary tract. These malformations frequently result in urinary tract infections, incontinence, renal damage and sexual dysfunction. Approximately one out of 20,000 newborns is affected by this rare disease which is considered to be one of the most severe forms of malformations on this spectrum. "Congenital classic bladder exstrophy thus represents an enormous challenge in the medical care of patients affected and their families," says Dr. Reutter.

Focus at the Center for Rare Diseases

To date, the genetic causes of this rare disease have been basically unknown. In the past ten years, with the bladder extrophy/epispadias self-help group and leading pediatric urologists and pediatric surgeons in Germany - including from the Barmherzigen Brder Pediatric Hospital in Regensburg as well as the universities of Mainz and Ulm - researchers at the University of Bonn hospital have been able to gather the largest group of patients in the world. The researchers in Bonn received additional support for the current study from researchers at the Max Planck Institute for Molecular Genetics in Berlin. Assistance was also provided by the Center for Rare Diseases at the University of Bonn Hospital (ZSEB). The researchers focus on rare uro-rectal malformations there.

Using blood samples from a total of 210 patients, the scientists isolated the genetic information and compared it with a control group of healthy persons. The researchers used automated analysis methods to record more than 700,000 genetic markers in each case which are evenly distributed throughout the DNA. The evaluation using biostatistical methods revealed a clear connection with an altered gene: ISL1, which is located on chromosome five. "In this way, a gene in connection with this disease was identified for the very first time," says Prof. Dr. Michael Ludwig from the Institute of Clinical Chemistry and Clinical Pharmacology of the University of Bonn Hospital.

The search for other genes

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Gene leads to malformation of the urinary tract

A multi-year, ongoing study suggests that a new kind of gene therapy for hemophilia B could be safe and effective for human patients. Published in the journal Science Translational Medicine, the research showed that a reprogrammed retrovirus could successfully transfer new factor IX (clotting) genes into animals with hemophilia B to dramatically decrease spontaneous bleeding. Thus far, the new therapy has proven safe.

"The result was stunning," said Timothy Nichols, MD, director of the Francis Owen Blood Research Laboratory at the University of North Carolina School of Medicine and co-senior author of the paper. "Just a small amount of new factor IX necessary for proper clotting produced a major reduction in bleeding events. It was extraordinarily powerful."

The idea behind gene therapy is that doctors could give hemophilia patients a one-time dose of new clotting genes instead of a lifetime of multiple injections of recombinant factor IX that until very recently had to be given several times a week. A new FDA-approved hemophilia treatment lasts longer than a few days but patients still require injections at least once or twice a month indefinitely.

This new gene therapy approach, like other gene therapy approaches, would involve a single injection and could potentially save money while providing a long-term solution to a life-long condition. A major potential advantage of this new gene therapy approach is that it uses lentiviral vectors, to which most people do not have antibodies that would reject the vectors and make the therapy less effective.

In human clinical studies, approximately 40 percent of the potential participants screened for a different kind of viral vector -- called adeno-associated viral vectors -- have antibodies that preclude them from entering AAV trials for hemophilia gene therapy treatment. This means that more people could potentially benefit from the lentivirus gene therapy approach.

Hemophilia is a bleeding disorder in which people lack a clotting factor, which means they bleed much more easily than people without the disease. Often, people with hemophilia bleed spontaneously into joints, which can be extremely painful and crippling. Spontaneous bleeds into soft tissues are also common and can be fatal if not treated promptly. Hemophilia A affects about one in 5,000 male births. These patients do not produce enough factor VIII in the liver. This leads to an inability to clot. Hemophilia B affects about one in 35,000 births; these patients lack factor IX.

This new method was spearheaded by Luigi Naldini, PhD, director of the San Raffaele Telethon Institute for Gene Therapy and co-senior author on the Science Translational Medicine paper.

For this study, Naldini and Nichols developed a way to use a lentivirus, which is a large retrovirus, to deliver factor IX genes to the livers of three dogs that have naturally occurring hemophilia. The researchers removed the genes involved in viral replication. "Essentially, this molecular engineering rendered the virus inert," Nichols said. "It had the ability to get into the body but not cause disease." This process turned the virus into a vector -- simply a vehicle to carry genetic cargo.

Unlike some other viral vectors that have been used for gene therapy experiments, the lentiviral vector is so large that it can carry a lot of payload -- namely, the factor IX genes that people with hemophilia B lack. (This approach could also be used for hemophilia A where the FVIII gene is considerably larger.)

These viral vectors were then injected directly into the liver or intravenously. After more than three years, the three dogs in the study experienced zero or one serious bleeding event each year. Before the therapy, the dogs experienced an average of five spontaneous bleeding events that required clinical treatment. Importantly, the researchers detected no harmful effects.

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New gene therapy for hemophilia shows potential as safe treatment

Amid rumours that precision gene-editing techniques have been used to modify the DNA of human embryos, researchers have called for a moratorium on the use of the technology in reproductive cells.

MOLEKUUL/SCIENCE PHOTO LIBRARY

The gene-editing technique CRISPR uses an enzyme (white) and RNA guides (blue) to cut DNA at a point specified by a DNA fragment (red).

In a Comment published on 12 March in Nature1, Edward Lanphier, chairman of the Alliance for Regenerative Medicine in Washington DC, and four co-authors call on scientists to agree not to modify human embryos even for research.

Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, write Lanphier and his colleagues, who include Fyodor Urnov, a pioneer in gene-editing techniques and scientist at Sangamo BioSciences in Richmond, California. Many groups, including Urnov's company, are already using gene-editing tools to develop therapies that correct genetic defects in people (such as by editing white blood cells). They fear that attempts to produce designer babies by applying the methods to embryos will create a backlash against all use of the technology.

Known as germline modification, edits to embryos, eggs or sperm are of particular concern because a person created using such cells would have had their genetic make-up changed without consent, and would permanently pass down that change to future generations.

We need a halt on anything that approaches germline editing in human embryos, Lanphier, who is also chief executive of Sangamo, told Natures news team.

But other scientists disagree with that stance. Although there needs to be a wide discussion of the safety and ethics of editing embryos and reproductive cells, they say, the potential to eliminate inherited diseases means that scientists should pursue research.

Geneticist Xingxu Huang of ShanghaiTech University in China, for example, is currently seeking permission from his institutions ethics committee to try genetically modifying discarded human embryos. In February 2014, he reported2 using a gene-editing technique to modify embryos that developed into live monkeys. Human embryos would not be allowed to develop to full term in his experiments, but the technique gives lots of potential for its application in humans, he says.

Besides Huangs work, gene-editing techniques are also being used by Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, to eliminate disease-causing mutations from mitochondria, the cell's energy-processing structures. Belmonte's work is on unfertilized eggs; human eggs with such modified mitochondria could one day be used in in vitro fertilization (IVF) procedures to prevent a woman's offspring from inheriting mitochondrial disease.

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Scientists sound alarm over DNA editing of human embryos