lunes, 24 de julio de 2017

Scientists uncover new gene therapy treatment routes for motor neurone disease

Scientists uncover new gene therapy treatment routes for motor neurone disease

News-Medical

Scientists uncover new gene therapy treatment routes for motor neurone disease

Scientists investigating the genetic causes and altered functioning of nerve cells in motor neurone disease (MND) have discovered a new mechanism that could lead to fresh treatment approaches for one of the most common forms of the disease.
The team, based in the Sheffield Institute for Translational Neuroscience (SITraN), investigated a mutation in one particular gene, which causes sections of DNA to replicate themselves inexplicably within cells. They found a way to prevent RNA, carrying these replicated sequences, from leaving the cell's nucleus and travelling into the surrounding cytoplasm where they cause cell death.
Patients with MND suffer progressive paralysis as the nerves supplying muscles degenerate. Although there are several different types of MND, this mutation, in a gene called C9ORF72, is responsible for the most common type of MND, called Amyotrophic Lateral Sclerosis (ALS). This accounts for about 40-50 per cent of inherited cases and 10 per cent of all MND cases. The mutations or environmental factors causing the vast majority of MND cases remain unknown.
DNA is produced in the cell's nucleus and contains the instructions which cells use to carry out their functions. Messenger RNA, called mRNA, transcribes this information and carries it out of the cell to 'protein factories' in the cytoplasm surrounding the nucleus.
It is quite common for some sections of repeated DNA stretches to replicate themselves for reasons that are poorly understood. These repetitions are 'non-coding' sections that are not responsible for building proteins and are edited out before they leave the nucleus to serve as templates for the production of proteins.
In this particular type of motor neurone disease, however, the RNA not only contains the unnecessary replicated sequences, it is able to take them out of nucleus and into the cell's cytoplasm. Once in the cytoplasm, the RNA is used to make up repeated proteins that clump together and block the normal function of the cell, causing it to die.
In an early stage study, published in Nature Communications, the researchers have been able to pinpoint why the repeated RNA sequences are able to leave the cell's nucleus to cause cell death.
The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door.
Working in partnership with researchers at the MRC Mitochondrial Biology Unit at the University of Cambridge, the team have shown that by targeting the SRSF1 protein, it is possible to reduce the amount of rogue RNA escaping into the cell's cytoplasm.
"This is a completely new approach to tackling the most common type of motor neurone disease. No one has yet attempted to prevent these repeated sequences of RNA from leaving the cell's nucleus and it opens up new areas of investigation for gene therapy," explains University of Sheffield's Dr Guillaume Hautbergue, who conceived the study and led the research jointly with Dr Alexander Whitworth, of the University of Cambridge, and SITraN Director, Professor Dame Pamela Shaw.
The team have been investigating ways to reduce the levels of SRSF1 in the cell, or to alter its makeup so that it is unable to interact with the cell's export machinery, reducing the amount of rogue RNA molecules to escape into the cell's cytoplasm. Instead, the RNA builds up in the nucleus, but eventually degrades as no adverse effects were observed within the nerve cells.
These methods have been successfully tested in the laboratory in nerve cells reprogrammed from patient's skins and in a fruitfly model of disease. New in vivo tests in mice, the closest model to human disease, are planned to start later this year.
"Repeated RNA transcripts are also present in other neurodegenerative diseases, including Huntington's Disease, Myotonic Dystrophy, Spinocerebellar Ataxias and Fragile X-associated Temor/Ataxia syndrome," added Dr Hautbergue. "Although we are at a very early stage in our research, it's possible that our approach could open up new possibilities for gene therapies for these diseases as well once we have investigated how the RNA molecules carrying the disease-specific replicated sequences leave the cell's nucleus to travel into the surrounding cytoplasm."

FDA advisory committee recommends Novartis' CAR-T therapy for young leukemia patients

FDA advisory committee recommends Novartis' CAR-T therapy for young leukemia patients

News-Medical

FDA advisory committee recommends Novartis' CAR-T therapy for young leukemia patients

Today the FDA's Oncologic Drugs Advisory Committee, an independent panel of experts, voted unanimously to recommend to the FDA approval of Novartis' experimental CAR-T therapy called Tisagenlecleucel, also known as CTL019. This form of gene therapy has demonstrated impressive results in hard-to-treat leukemia (ALL) pediatric and adolescent patients who have relapsed or whose cancers have proven resistant to other treatment. One of the panelists Dr. Timothy Cripe of Nationwide Children's Hospital remarked, "this is the most exciting therapy I have seen in my lifetime."
This advisory committee hearing was the last major regulatory milestone before the agency decides in September whether or not to approve the treatment, which would make Novartis' CAR-T therapy the first-ever gene therapy treatment approved by the FDA in US markets. The committee's unanimous positive vote will go a long way towards that approval.
ACGT fellow, Dr. Carl June of the University of Pennsylvania, was a leader in developing CTL019 therapy and a pioneer of the novel concept to use a patient's own T cells and genetically modify them to attack the cancer cells. The protocol involves removing a patient's white blood cells called T-cells, genetically modifying them, then infusing the newly transformed cells back into the patient's body following chemotherapy. This process gives the patient's immune system a tumor-attack roadmap for the treatment of leukemia and other cancers, including those of the ovaries and myeloma. Dr. June was one of the first scientists to demonstrate the use of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors.
Dr. June received two grants from ACGT in 2004 and 2008 for his studies in CAR-T therapy for lymphoma and leukemia, and ovarian cancers. On August 10, 2011, Dr. June's study results were reported in the New England Journal of Medicine and Science Translational Medicine. The results exceeded everyone's wildest expectations.
"The funds from ACGT sustained us. When other organizations, including the NIH, considered gene therapy too risky, ACGT believed in the science and funded us when no one else would," said Dr. June. "ACGT really kept us going and kept the research alive. Without them, we wouldn't have had a clinical trial and I don't think we'd be where we are today."
"In the early 2000's when ACGT was founded, gene therapy was an outlier," noted ACGT co-founder Barbara Netter, who founded ACGT with her late husband Edward in 2001. "Scientists believed in the promise of gene therapy, but after the death of a patient in a clinical trial in 1999, organizations were reluctant to fund this type of work. ACGT believed so strongly in cell and gene therapy and moved to embrace the science, that it focused all its resources on helping scientists we thought had the most exciting, novel ideas on how to treat cancers. Dr. June was one of those scientists and we were very excited about the potential of his work even back in 2004 when he received his first grant from ACGT."
In a Novartis' sponsored ELIANA study, which formed the basis of Novartis' application of approval, treatment with Tisagenlecleucel resulted in a best overall response rate of 83%, with 63% of successfully infused patients experiencing a complete response. Beyond representing a change in the treatment of relapsed/refractory ALL, approval for Tisagenlecleucel would be a landmark decision -- ushering in CAR-T as a new class of personalized cancer treatments. A regulatory approval would also put Novartis at the head of that class, further than other bio-pharma rivals.
"This review by the FDA of CAR-T therapy is a major milestone in the successful treatment of cancer," noted John Walter, CEO and president of ACGT. "If approved, it will be the first-ever true gene therapy treatment made available to the US population and will help accelerate the speed at which we will see even more gene-based therapies come to fruition. It's a very exciting time."

Researchers discover gene mutations that worsen respiratory infections among children

Researchers discover gene mutations that worsen respiratory infections among children

News-Medical

Researchers discover gene mutations that worsen respiratory infections among children

Researchers funded by the Swiss National Science Foundation (SNSF) have discovered mutations that worsen respiratory infections among children. Their study explains the mechanism involved.
Colds that are not linked to influenza are generally benign. Still, 2% of each generation of children have to go to hospital following a virulent infection. "These respiratory problems are responsible for 20% of child mortality around the world", says Jacques Fellay, who has held an SNSF professorship since 2011. "It is truly a silent epidemic."
An international research collaboration coordinated by Fellay has discovered the reason for some of these infections: they are caused by mutations of a gene that plays a part in recognizing certain cold-inducing viruses.
"We have been able to confirm that a gene, called IFIH1, plays an important role in defending the body against the principal viruses responsible for respiratory infections among children", he explains. This gene normally helps in identifying the virus's RNA, a type of genetic information related to the DNA. "We have been able to isolate the mechanisms that prevent the immune systems of children with an IFIH mutation from successfully combating the viral infection."
Hospitals in Switzerland and Australia
The researchers collaborated with various pediatric wards in Swiss and Australian hospitals to study cases of children who needed intensive care after a severe respiratory infection (bronchiolitis or pneumonia) caused by a virus. They excluded premature babies and children with chronic illnesses in order to focus on the genetic causes. The result: of the 120 children included in the study, eight carried mutations of the IFIH1 gene.
"This gene encodes a protein which recognizes the presence of a certain number of cold-inducing microbes in a cell, such as the respiratory syncytial virus (RSV) or rhinoviruses", explains Samira Asgari of EPFL, who designed the experiments. "They attach themselves to the germ's RNA and trigger a cascade of molecular signals that provoke an effective immune reaction." The researcher has been able to show that three different mutations of IFIH1 render the protein incapable of recognizing the virus, thereby preventing the body from defending itself against the infection.
In 2015, Jacques Fellay had already studied the genome of more than 2000 patients and statistically shown which genetic variations influence our capacity to defend ourselves against common viral infections. "The two approaches are complementary", says Fellay. "A study covering a large number of subjects, like the one in 2015, makes it possible to identify the relevant genes across the entire population; but their variations have only a limited impact on individuals. In contrast, a study focusing on carefully selected patients enables you to investigate mutations that are more rare but also more critical for the patient, and to pinpoint the mechanisms in play."
Prevention and therapy
These results should prove useful for setting new therapeutic and preventive targets: "At their parents' request, we also tested the siblings of some of the children carrying the mutation to see if they too are more fragile when it comes to infections. If this is the case, parents may decide to keep their child at home during an epidemic, or to go to hospital double-quick if the child catches a cold."
For Jacques Fellay, this research work aptly illustrates the methods and objectives of personalized medicine or 'precision medicine': "Our bodies' capacity to ward off illnesses can vary greatly. A better understanding of the genetic mechanisms that create these differences will lead to more targeted prevention and therapy. One scenario might involve genetic screening to determine the degree of susceptibility to infections; this could be included in the blood tests that are routinely performed just after birth. But society would need to have a say in deciding which genetic tests are desirable."

Study seeks to understand genetic synergy in cleft palate

Study seeks to understand genetic synergy in cleft palate

News-Medical

Study seeks to understand genetic synergy in cleft palate

Like all of the individual elements of fetal development, palate growth is a marvel of nature. In part of this process, ledges of tissue on the sides of the face grow downwards on each side of the tongue, then upward, fusing at the midline at the top of the mouth. The vast majority of the time, this process goes correctly. However, some part of it goes awry for the 2,650 babies born in the United States each year with cleft palates and the thousands more born worldwide with the defect.
For nearly two decades, researchers have known that a gene known as IRF6 is involved in palate formation. Studies have shown that this gene contributes about 12 percent to 18 percent of the risk of cleft palate, more than any other gene identified thus far. IRF6 is active in epithelial tissues -- those that line cavities and surfaces throughout the body -- including the periderm, a tissue that lines the mouth cavity and plays an important role during development.
According to Youssef A. Kousa, M.S., D.O., Ph.D., a child neurology fellow at Children's National Health System, the periderm acts like a nonstick layer, preventing the tongue or other structures from adhering to the growing palate and preventing it from sealing at the midline. While researchers have long suspected that IRF6 plays a strong role in promoting this nonstick quality, exactly how it exerts its influence has not been clear.
"Gaining a better understanding of this gene might help us to eventually address deficits or perturbations in the system that creates the palate," Dr. Kousa says. "Like a mechanic fixing a faulty engine, we will not be able to remedy problems related to this gene until we know how the gene works."
In a study published July 19, 2017 by Journal of Dental Research, Dr. Kousa and colleagues seek to decipher one piece of this puzzle by investigating how this key gene might interact with others that are active during fetal development. The researchers were particularly interested in genes that work together in a cascade of activity known as the tyrosine kinase receptor signaling pathway.
Because this pathway includes a large group of genes, Dr. Kousa and colleagues reasoned that they could answer whether IRF6 interacts with this pathway by looking at whether the gene interacts with the last member of the cascade, a gene called SPRY4. To do this, the researchers worked with experimental models that had mutations in IRF6SPRY4 or both. If these two genes interact, the scientists hypothesized, carrying mutations in both genes at the same time should result in a dramatically different outcome compared with animals that carried mutations in just one gene.
Using selective breeding techniques, the researchers created animals that had mutations in either of these genes or in both. Their results suggest that IRF6 and SPRY4 indeed do interact: Significantly more of the oral surface was adhered to the tongue during fetal development in experimental models that had mutations in both genes compared with those that had just one single gene mutated. Examining the gene activity in the periderm cells of these affected animals, the researchers found that doubly mutated experimental models also had decreased activity in a third gene known as GRHL3, which also has been linked with cleft lip and palate.
Dr. Kousa says the research team plans to continue exploring this interaction to better understand the flow of events that lead from perturbations in these genes to formation of cleft palate. Some of the questions they would like to answer include exactly which gene or genes in the tyrosine kinase receptor signaling pathway specifically interact with IRF6 -- since SPRY4 represents just the end of that pathway, others genes earlier in the pathway are probably the real culprits responsible for driving problems in palate formation. They also will need to verify if these interactions take place in humans in the same way they occur in preclinical models.
Eventually, Dr. Kousa adds, the findings could aid in personalized prenatal counseling, diagnosis, and screening related to cleft palate, as well as preventing this condition during pregnancy. Someday, doctors might be able to advise couples who carry mutations in these genes about whether they are more likely to have a baby with a cleft palate or determine which select group of pregnancies need closer monitoring. Additionally, because research suggests that GRHL3 might interact with nutrients, including inositol, it might be possible to prevent some cases of cleft palate by taking additional supplements during pregnancy.
"The more we know about how these genes behave," Dr. Kousa says, "the more we can potentially avoid fetal palate development going down the wrong path."

Genetics plays major role in how infants visually explore social world, twin study reveals

Genetics plays major role in how infants visually explore social world, twin study reveals

News-Medical

Genetics plays major role in how infants visually explore social world, twin study reveals

New research has uncovered compelling evidence that genetics plays a major role in how children look at the world and whether they have a preference for gazing at people's eyes and faces or at objects.
The discovery by researchers at Washington University School of Medicine in St. Louis and Emory University School of Medicine in Atlanta adds new detail to understanding the causes of autism spectrum disorder. The results show that the moment-to-moment movements of children's eyes as they seek visual information about their environment are abnormal in autism and under stringent genetic control in all children.
The study is published online July 12 in the journal Nature.
"Now that we know that social visual orientation is heavily influenced by genetic factors, we have a new way to trace the direct effects of genetic factors on early social development, and to design interventions to ensure that children at risk for autism acquire the social environmental inputs they need to grow and develop normally," said lead author John N. Constantino, MD, the Blanche F. Ittleson Professor of Psychiatry and Pediatrics at Washington University. "These new findings demonstrate a specific mechanism by which genes can modify a child's life experience. Two children in the same room, for example, can have completely different social experiences if one carries an inherited tendency to focus on objects while the other looks at faces, and these differences can play out repeatedly as the brain develops early in childhood."
The researchers studied 338 toddlers ages 18 to 24 months using eye-tracking technology, developed at Emory, allowing them to trace young children's visual orientation to faces, eyes or objects as the children watched videos featuring people talking and interacting.
The children, who were part of the Missouri Family Registry, a database of twins that is maintained at Washington University School of Medicine, included 41 pairs of identical twins -; such twins share 100 percent of their DNA -; and 42 sets of fraternal twins -; who share only about 50 percent of their DNA. In addition, the researchers studied 84 unrelated children and 88 children diagnosed with autism spectrum disorder.
Constantino, with fellow investigators Warren R. Jones, PhD, and Ami Klin, PhD, of Emory University School of Medicine, evaluated the eye-tracking data. Each twin was tested independently, at different times, without the other twin present.
How much one identical twin looked at another person's eyes or face was almost perfectly matched by his or her co-twin. But in fraternal twins, eye movements in one twin accounted for less than 10 percent of the variation in the eye movements of his or her co-twin. Identical twins also were more likely to move their eyes at the same moments in time, in the same directions, toward the same locations and the same content, mirroring one another's behavior to within as little as 17 milliseconds. Taken together, the data indicate a strong influence of genetics on visual behavior.
"The moment-to-moment match in the timing and direction of gaze shifts for identical twins was stunning and inferred a very precise level of genetic control," said Constantino, who directs the William Greenleaf Eliot Division of Child and Adolescent Psychiatry at Washington University. "We have spent years studying the transmission of inherited susceptibility to autism in families, and it now appears that by tracking eye movements in infancy, we can identify a key factor linked to genetic risk for the disorder that is present long before we can make a clinical diagnosis of autism."
The effects persisted as the children grew. When the twins were tested again about a year later, the same effects were found: Identical twins remained almost perfectly matched in where they looked, but fraternal twins became even more different than they were when initially evaluated.
Autism spectrum disorder is a lifelong condition that affects about 1 in 68 children in the United States. It is known to be caused by genetic factors, and earlier work by the Emory University team had shown that babies who look progressively less at people's eyes, beginning as early as 2-6 months of age, have an elevated risk for autism. Meanwhile, Constantino and others in the group have studied how subtle behaviors and symptoms that characterize autism aggregate in the close relatives of individuals with autism, as a way to identity inherited susceptibilities that run in families and contribute to autism risk.
"Studies like this one break new ground in our understanding of autism spectrum disorder: Establishing a direct connection between the behavioral symptoms of autism and underlying genetic factors is a critical step on the path to new treatments," said Lisa Gilotty, PhD, chief of the Research Program on Autism Spectrum Disorders at the National Institute of Mental Health, which provided support for the study in tandem with the Eunice Kennedy Shriver Institute of Child Health and Human Development.
Those new treatments could include interventions that motivate very young children to focus their gazes more on faces and less on objects.
"Testing infants to see how they are allocating visual attention represents a new opportunity to evaluate the effects of early interventions to specifically target social disengagement, as a way to prevent the most challenging disabilities associated with autism," said senior author Warren R. Jones, PhD, director of autism research at the Marcus Autism Center at Emory. "Such interventions might be appropriate for infants showing early signs of risk or those who have been born into families in which autism has affected close relatives. In addition, learning why some infants who tend to not look at eyes and faces develop without social disability is another priority."
The small percentage of healthy children who tended to avoid looking at eyes and faces may provide researchers with insight on how to successfully compensate for those tendencies and therefore inform the development of higher-impact interventions that will produce the best possible outcomes for infants with inherited susceptibility to autism.

Genetics of Hitchhiker's Thumb

Genetics of Hitchhiker's Thumb

News-Medical

Genetics of Hitchhiker's Thumb

Hitchhiker's thumb is otherwise known as distal hyperextensibility of the thumb. This is because of the genetic traits that make a person bend his thumb backward while stretching.
The distal joint plays an important role in keeping the thumb straight. When the distal joint hyperextends, it enables the thumb to bend backward, creating the hitchhiker's thumb. Having a hitchhiker's thumb is neither an advantage nor a disadvantage. This type of bending does not affect the functions of the thumb nor causes any pain to it.

Bendy Thumb Gene

In the human genetic pattern, there are a number of genes that determine the size, shape, and color of a person. The gene that controls the extendibility of the thumb is known as the "Bendy thumb gene." The bendy thumb gene comprises of multiple alleles in the chromosomes. One allele from the bendy thumb gene can produce a straight thumb and another allele may produce a hitchhiker's thumb. It all depends on what allele people receive from their parents.
Thumbs ranging from straight to hitchhiker. Image Credit: Myths of Human GeneticsJohn H. McDonald, University of Delaware
Thumbs ranging from straight to hitchhiker. Image Credit: Myths of Human Genetics John H. McDonald, University of Delaware

Phenotype

The group of genes that is responsible for a trait is known as a genotype, with the characteristic of that particular trait called a phenotype. Hitchhiker's thumb is not to be considered as a genetic condition or disorder, but is a result of the phenotype. Phenotype consists of traits that influence the appearance and behavior of a person. Traits are alleles that help in the formation of chromosomes and fall into two categories: dominant traits and recessive traits.
  • Dominant traits: When alleles combine together, some become stronger than the others. This stronger allele is responsible for the dominant trait. A person with dominant traits will have a straight thumb, which can only be folded toward the palm.
  • Recessive Traits: Dominant alleles can be found in all organisms. In case the dominant allele fails to show its presence, the recessive allele will be expressed. These are known as recessive traits. A person with recessive traits will have a hitchhiker thumb that can be folded to the back of the hand. Meanwhile, a person has a hitchhiker thumb only when he receives two recessive alleles from the parents.
Let us assume “S” to be the dominant allele and “s” to be the recessive allele. If a person is born with the “ss” genotype, then they will have a hitchhiker's thumb. A person born with the “Ss” genotype will have a straight thumb, but will also be a bearer of the hitchhiker's thumb. A person born with an "SS" genotype will only have a straight thumb and no chances for having the condition of the hitchhiker.

Conditions that Cause Hitchhiker's Thumb

Joint Hypermobility and Diastrophic Dysplasia are conditions associated with Hitchhiker's thumb.
  • Joint Hypermobility: Joint Hypermobility is a condition in which people are able to move their joints and limbs to an extent that normal people find difficult.  This condition is affected by the genes that are transferred to the person by his parents. Genetically, hypermobility is determined by the change that occurs in collagen, an abundant protein found in the skin, muscle, and bones. When collagen becomes weak, it will lead to loose and flexible joints and ligaments.
A person with hypermobility feels pain in the joints of his fingers, knees, and elbows.  This condition is often found in young people and children. It is a common condition and hence does not require any treatment, unless the frequency of the pain in the joint is very high.
  • Diastrophic dysplasia: Diastrophic dysplasia is also known as diastrophic dwarfism. This is known to be an infrequent condition, formed at the time of birth. The diastrophic dysplasia creates a disorder in the development of the bones and the cartilage. The diastrophic dysplasia sulfate transporter (DTDST) gene is responsible for the formation of this condition. DTDST is located at the arm structure in the chromosomes.
This condition includes abnormal spine curvature, short legs and arms, upward-turning foot, and unusually bending thumbs or the hitchhiker's thumb.
Genetic disorders and defects are possible to occur at any stage during pregnancy. Most of the disorders tend to affect the baby before the third month (the time during which the formation of the organs occurs). Although hitchhikers is genetic, the parents are not always responsible for this defect in the child. If both the parents have straight thumbs, there is a lowered chance for the child to get affected by hitchhiker’s thumb.
If one parent has hitchhiker's thumb while the other has a straight thumb, there are possibilities for the child to get either of the (straight or hitchhiker) thumb structures. In some cases, there are also chances for the child to be born with disorders, even though the mother and father are free of any genetic risks.
Last Updated: Jul 18, 2017

Study identifies new gene involved in Fanconi anemia

Study identifies new gene involved in Fanconi anemia

News-Medical

Study identifies new gene involved in Fanconi anemia

Researchers from the group led by UAB Chair Professor Dr Jordi Surrallés at the Hospital de la Santa Creu i Sant Pau, Barcelona, the Universitat Autònoma de Barcelona and the CIBER of Rare Diseases (CIBERER) participated in a study which has led to the identification of a new gene involved in Fanconi anemia, a rare genetic disease.
The authors of the study, published in the prestigious The Journal of Clinical Investigation, discovered specific mutations in the RFWD3 gene, related to DNA repair, which are involved in the development of this disorder. For this reason, researchers chose to use next-generation massive sequencing technology in the study.
Fanconi anemia is a hereditary disease caused by mutations in some of the genes related to DNA repair, a process which is essential for the maintenance of stem cells and the prevention of cancer. People affected by this serious disorder suffer from bone marrow failure, several congenital defects and have more chances of developing solid tumors and haematologic problems.
The authors of the research detected mutations in the RFWD3 gene in a child with Fanconi anemia. They also confirmed the relation between the mutations and the disorder with functional studies in cell and animal models.
The research was coordinated by Dr Detlev Schindler of the University of Würzburg, Germany. Participating were other researchers from the same university and from the University of Kyoto, as well as the group led by Dr Surrallés, Chair Professor in Genetics at the Universitat Autònoma de Barcelona, head of the CIBERER research group and current director of the Genetics Unit at the Hospital de la Santa Creu i Sant Pau.
Until now, there was knowledge of 21 genes involved in Fanconi anemia. Three years ago, the research group coordinated by Dr Surrallés had already directed a study which gave way to the discovery of another of the genes causing this disorder, the FANCQ. The study was published in the American Journal of Human Genetics.
"The discovery of new genes is essential not only for genetic diagnosis and advice, but also for the development of new therapies. A good example is gene therapies in which we are already working on the clinical trials. The RFWD3 protein is of the few deficient proteins in patients with Fanconi anemia in which we can see a clear enzymatic activity (ubiquitin ligase), which opens the door to massive drug screenings. In this sense, my group has already worked on several screenings of thousands of therapeutic molecules with the aim of repositioning a drug for this disease", Dr Surrallés explains.

'Organic gene therapy' could be effective treatment approach for serious blood disorders

'Organic gene therapy' could be effective treatment approach for serious blood disorders

News-Medical



'Organic gene therapy' could be effective treatment approach for serious blood disorders

Genome therapy with beneficial natural mutation could lead to new treatment for life-threatening blood disorders.
By introducing a beneficial natural mutation into blood cells using the gene-editing technique CRISPR, a UNSW Sydney-led team of scientists has been able to switch on production of fetal hemoglobin - an advance that could eventually lead to a cure for sickle cell anemia and other blood disorders.
People with thalassaemia or sickle cell anemia have damaged adult hemoglobin - the vital molecule that picks up oxygen in the lungs and transports it around the body - and they require life-long treatment with blood transfusions and medication.
However, people with these diseases who also carry the beneficial natural mutation - known as British-198 - have reduced symptoms, because the mutation switches on the fetal hemoglobin gene that is normally turned off after birth.
The extra fetal hemoglobin in their blood, which has a very strong affinity for oxygen, does the work of the defective adult hemoglobin.
"With CRISPR gene-editing we can now precisely cut and alter single genes within our vast genome," says study senior author and UNSW molecular biologist Professor Merlin Crossley.
"Our laboratory has shown that introducing the beneficial mutation British-198 into blood cells using this technology substantially boosts their production of fetal hemoglobin.
"Because this mutation already exists in nature and is benign, this 'organic gene therapy' approach should be effective and safe to use to treat, and possibly cure, serious blood disorders. However, more research is still needed before it can be tested in people," he says.
The study by scientists from UNSW, the Japanese Red Cross Society and the RIKEN BioResource Centre in Japan, is published in the journal Blood.
The beneficial British-198 mutation, which was first identified in a large British family in 1974, involves a change in just a single letter of the genetic code.
Carriers of this mutation have fetal hemoglobin levels as high as 20 per cent of total hemoglobin, while most people's fetal hemoglobin levels fall to about 1 per cent of total hemoglobin after birth.
The researchers also discovered how this British-198 mutation works. They found it creates a new binding site for a protein called KLF1 that turns blood genes on.
Mutations affecting adult hemoglobin production are among the most common of all genetic variations, with about 5 per cent of the world's population carrying a defective gene.
"To turn the new gene editing approach into a therapy for blood disorders, the British-198 mutation would have to be introduced into blood-forming stem cells from the patient," says Professor Crossley.
"A large number of stem cells would have to be edited in order to repopulate the patients' blood with genetically enhanced cells."

New partnership to advance novel airway-delivered gene therapy for treating pulmonary hypertension

New partnership to advance novel airway-delivered gene therapy for treating pulmonary hypertension

News-Medical

New partnership to advance novel airway-delivered gene therapy for treating pulmonary hypertension

Mount Sinai has partnered with Theragene Pharmaceuticals, Inc. to advance a novel airway-delivered gene therapy for treating pulmonary hypertension (PH), a form of high blood pressure in blood vessels in the lungs that is linked to heart failure. If the therapy succeeds in human clinical trials, it will provide patients for the first time with a way to reverse the damage caused by PH.
This gene therapy technique comes from the research of Roger J. Hajjar, MD, Professor of Medicine and Director of the Cardiovascular Research Center at the Icahn School of Medicine at Mount Sinai, and has been proven effective in rodent and pig animal models. PH is a deadly disease that disproportionately affects young adults and women; 58 percent of cases are found in young adults and 72 percent are women. There is currently no effective cure for PH, and about 50 percent of people who are diagnosed will die from the disease within five years.
PH is a rare (15-50 cases per million people), rapidly progressing disease that occurs when blood pressure is too high in vessels leading from the heart to the lungs. The high pressure is caused by abnormal remodeling of the lung blood vessels, characterized by a proliferation of smooth muscle cells and a thickening and narrowing of these vessels, and can lead to failure of the right ventricle of the heart and premature death. Abnormalities in calcium cycling within the vascular cells play a key role in the pathophysiology of pulmonary hypertension, along with deficiencies in the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) protein which regulates intracellular calcium within these vascular cells and prevents them from proliferating within the vessel wall. Downregulation of SERCA2a leads to the proliferative remodeling of the vasculature. This gene therapy, delivered via an inhaled aerosolized spray, aims to increase the expression of SERCA2a protein, and has been shown in rodents and pigs to improve heart and lung function, as well as reduce and even reverse cellular changes caused by PH.
"This is a devastating disease, and our work in collaboration with many laboratories across the country has allowed us to identify a specific molecular target and use gene therapy to improve cardiovascular and lung parameters in experimental models of PH. We look forward to starting first-in-human studies using this approach in affected patients," said Dr. Hajjar, the senior author of the studies, highlighting that clinical trials will be underway in the next two years. It may take several years before a product is commercially available for PH patients.
"We are excited about the potential for SERCA2a gene therapy as a new modality in treating this serious disease," said Jon Berglin, Chief Executive Officer of Theragene Pharmaceuticals, Inc. "We look forward to develop and advance this promising product into the clinic."
"This represents another critical advancement in a potentially transformative therapeutic breakthrough by Mount Sinai scientists, demonstrating our commitment to improving health outcomes. We are thrilled to be working with Theragene Pharmaceuticals, and continue to strengthen our expertise in partnering health care innovations with industry," said Erik Lium, PhD, Senior Vice President of Mount Sinai Innovation Partners, the commercialization arm of the Icahn School of Medicine at Mount Sinai.