Category Archives: Gene therapy

Date:

October 8, 2014

Source:

NIH/National Institute of Allergy and Infectious Diseases

Summary:

Gene therapy using a modified delivery system, or vector, can restore the immune systems of children with X-linked severe combined immunodeficiency (SCID-X1), a rare, life-threatening inherited condition that primarily affects boys, researchers have discovered.

Researchers have found that gene therapy using a modified delivery system, or vector, can restore the immune systems of children with X-linked severe combined immunodeficiency (SCID-X1), a rare, life-threatening inherited condition that primarily affects boys. Previous efforts to treat SCID-X1 with gene therapy were initially successful, but approximately one-quarter of the children developed leukemia two to five years after treatment. Results from a study partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), suggest that the new vector is equally effective at restoring immunity and may be safer than previous approaches.

In SCID-X1, mutations in a specific gene prevent the development of infection-fighting T cells. The standard therapy for SCID is transplantation of blood-forming stem cells, but some patients lack a suitable donor. In gene therapy, doctors remove stem cells from the patient's bone marrow, use a vector to insert a corrected gene and then return the corrected cells to the patient. Scientists suspect that the vectors used in earlier studies may have activated genes that control cell growth, contributing to leukemia.

In the current study, nine boys with SCID-X1 underwent gene therapy using a vector engineered by the study researchers. Seven boys developed functional T cells at levels comparable to those seen in previous studies and have remained healthy for one to three years after treatment. Analyses of the children's T cells suggest that the new vector causes fewer genomic changes that could be linked to leukemia. Researchers will continue to monitor the boys for leukemia development. Of the two other boys, one died of a pre-existing viral infection shortly after receiving the therapy, and one failed to develop corrected T cells and was given a stem cell transplant from an unrelated donor.

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Gene therapy shows promise for severe combined immunodeficiency

Joint research projects by NUIG and the Mayo Clinic will focus on a number of key strategic areas, including adult stem-cell therapy, gene therapy, biomaterials and biomedical engineering, the two institutes have said. Illustration: Getty

NUI Galway and the Mayo Clinic in the US plan to collaborate on clinical trials using regenerative medicine, following the signing of a memorandum of understanding between the two institutes.

The joint research projects will focus on a number of key strategic areas, including adult stem-cell therapy, gene therapy, biomaterials and biomedical engineering, the two institutes have said.

The Mayo Clinic and NUIGs Regenerative Medicine Institute have worked closely with each other for a number of years.

Both have licensed cell manufacturing facilities, and student and staff exchange programmes between Galway and the US will continue.

Welcoming the agreement, NUIG president Dr Jim Browne has noted that his university has Irelands only facility licensed to produce stem cells for human use.

A new clinical and translational research facility for conducting clinical trials with patients will be complete in early 2015, he said.

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NUI Galway in joint stem cell project with Mayo Clinic

Many human diseases are caused by defective genes.

All of these diseases are caused by a defect at a single gene locus. (The inheritance is recessive so both the maternal and paternal copies of the gene must be defective.) Is there any hope of introducing functioning genes into these patients to correct their disorder? Probably.

Other diseases also have a genetic basis, but it appears that several genes must act in concert to produce the disease phenotype. The prospects of gene therapy in these cases seems far more remote.

It is a disease of young children because, until recently, the absence of an immune system left them prey to infections that ultimately killed them.

Once the virus has infected the target cells, this RNA is reverse transcribed into DNA and inserted into the chromosomal DNA of the host.

The first attempts at gene therapy for SCID children (in 1990), used their own T cells (produced following ADA-PEG therapy) as the target cells.

In June of 2002, a team of Italian and Israeli doctors reported on two young SCID patients that were treated with their own blood stem cells that had been transformed in vitro with a retroviral vector carrying the ADA gene. After a year, both children had fully-functioning immune systems (T, B, and NK cells) and were able to live normal lives without any need for treatment with ADA-PEG or immune globulin (IG). The doctors attribute their success to first destroying some of the bone marrow cells of their patients to "make room" for the transformed cells.

Nine years later (August 2011) these two patients are still thriving and have been joined by 28 other successfully-treated children most of whom no longer need to take ADA-PEG.

Gene therapy has also succeeded for 20 baby boys who suffered from another form of severe combined immunodeficiency called X-linked SCID because it is caused by a mutated X-linked gene encoding a subunit called c (gamma-c) of the receptor for several interleukins, including interleukin-7 (IL-7).

IL-7 is essential for converting blood stem cells into the progenitors of T cells. [View]. Boys with X-linked SCID can make normal B cells, but because B cells need T-helper cells to function, these boys could make neither cell-mediated nor antibody-mediated immune responses and had to live in a sterile bubble before their treatment.

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Gene Therapy I - RCN Corporation

A gene-therapy experiment at Fred Hutchinson Cancer Research Center only involved a handful of brain-tumor patients, and on average, extended their lives by months, not years.

Even so, it was the first real progress in 30 years for patients with glioblastoma, the most common and most aggressive type of primary brain tumor the type that killed U.S. Sen. Edward Kennedy within 15 months of diagnosis.

I think this is actually one of those proof-of-concept milestones, said Dr. Stanton Gerson, director of the Case Comprehensive Cancer Center at Case Western Reserve University in Cleveland, who was not involved in the study. This is the very first clinical validation that all that science made sense.

The new approach, led by Dr. Hans-Peter Kiem and Dr. Jennifer Adair at Fred Hutch in Seattle, was published Friday in The Journal of Clinical Investigation.

It began with the usual therapy for such tumors powerful chemotherapy combined with a drug that disables a protein that makes some of these tumors particularly resistant to chemotherapy. More than half the patients with glioblastomas, including all seven patients enrolled in the study, have such a protein, Kiem said.

The protein-disabling drug, benzylguanine, is critically important because it allows chemotherapy to attack the tumor. But the drug also damages bone marrow, killing blood cells so people are left vulnerable to infection and bleeding, he said. For that reason, patients typically can receive only one or two cycles of chemotherapy.

The gene-therapy approach involved taking the patients stem cells and engineering them to become resistant to benzylguanine, so their blood cells werent damaged by the drug. When the stem cells were returned to the patients, their blood was protected but their tumors were left vulnerable to the chemotherapy.

Better protected against infection and bleeding, the seven patients in the study were able to receive more cycles of chemotherapy.

We can sensitize the tumor, while the blood cells are resistant, Kiem said. That is the trick.

Typical median survival for glioblastoma patients with the tumor-protecting protein is less than 13 months. The patients in this study, on average, survived 20 months, and all survived beyond one year. This is quite remarkable, he said.

Excerpt from:
Experiment at Fred Hutch raises hopes in battling brain tumors

A major hurdle in gene therapy is the efficient integration of a corrected gene into a patient's genome without mutating off-target sites. In a paper published today in Genome Research, scientists have used CRISPR/Cas genome editing technology to seamlessly and efficiently correct disease-causing mutations in cells from patients with -thalassemia.

-thalassemia results from inherited DNA mutations in the hemoglobin beta (HBB) gene, resulting in reduced HBB expression in red blood cells and, in the most severe forms, anemia. The only established curative treatment is hematopoietic stem cell transplantation; however, this treatment requires a matched donor. Gene therapy, which delivers a corrected copy of a gene into patient cells, could bypass the need for a donor. Previous attempts using a virus to randomly insert a normal gene into the genome has been successful in one -thalassemia patient, but the long-term effect of viral insertion is not yet known.

To correct HBB mutations directly in a patient's genome, researchers first generated induced pluripotent stem cells, or iPSCs, from skin cells of patients. The real breakthrough came when they applied CRISPR/Cas9 to precisely engineer a double strand DNA break at the HBB locus in these cells, allowing a donor plasmid with the corrected sites to be efficiently integrated, thus replacing the mutated sites. The donor plasmid also contained selectable markers to identify cells with corrected copies of the gene. These selectable markers were subsequently removed with transposase and a second round of selection, generating a seamless, corrected version of HBB in the patient's genome.

Importantly, the researchers could differentiate the corrected iPSCs into mature blood cells, and these blood cells showed restored expression of hemoglobin. However, much work is needed before these cells could be transplanted back into a patient for treating -thalassemia. "Although we and others are able to differentiate iPSCs into blood cell progenitors as well as mature blood cells, the transplantation of the progenitors into mouse models to test them has so far proven very difficult," said senior author Yuet Wai Kan from the University of California, San Francisco. "I believe it will take quite a few more years before we can apply it in a clinical setting."

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The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.

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Seamless gene correction of beta-thalassemia mutations in patient-specific cells

WASHINGTON No batteries required: Scientists are developing a biological pacemaker by injecting a gene into the hearts of sick pigs that changed ordinary cardiac cells into a special kind that induces a steady heartbeat.

The study, published on Wednesday, is one step toward developing an alternative to electronic pacemakers, which are implanted in 300,000 Americans a year.

There are people who desperately need a pacemaker but can't get one safely, said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. This development heralds a new era of gene therapy that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells it's about the size of a peppercorn, Marban said that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when you're active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For more than a decade, teams of researchers have worked on a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marban's attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs' hearts are so similar to human hearts, Marban's team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene called TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs' hearts in a spot that doesn't normally initiate heartbeats and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didn't receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

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Trying gene therapy to create biological pacemaker

Washington No batteries required: Scientists are creating a biological pacemaker by injecting a gene into the hearts of sick pigs that changed ordinary cardiac cells into a special kind that induces a steady heartbeat.

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans a year.

There are people who desperately need a pacemaker but cant get one safely, said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. This development heralds a new era of gene therapy that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells its about the size of a peppercorn, Marban says that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when youre active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For over a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marbans newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs hearts are so similar to human hearts, Marbans team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs hearts in a spot that doesnt normally initiate heartbeats and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didnt receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

Excerpt from:
Scientists use gene therapy to create biological pacemaker

WASHINGTON --

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans a year.

"There are people who desperately need a pacemaker but can't get one safely," said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. "This development heralds a new era of gene therapy" that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells - it's about the size of a peppercorn, Marban says - that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when you're active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For over a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marban's newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs' hearts are so similar to human hearts, Marban's team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs' hearts - in a spot that doesn't normally initiate heartbeats - and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didn't receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

More:
Scientists using gene therapy to create biological pacemaker

By LAURAN NEERGAARD AP Medical Writer

WASHINGTON (AP) - No batteries required: Scientists are creating a biological pacemaker by injecting a gene into the hearts of sick pigs that changed ordinary cardiac cells into a special kind that induces a steady heartbeat.

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans a year.

"There are people who desperately need a pacemaker but can't get one safely," said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. "This development heralds a new era of gene therapy" that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells - it's about the size of a peppercorn, Marban says - that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when you're active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For over a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marban's newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs' hearts are so similar to human hearts, Marban's team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs' hearts - in a spot that doesn't normally initiate heartbeats - and tracked them for two weeks.

Continued here:
Trying gene therapy to create biological pacemaker - Quincy Herald-Whig | Illinois & Missouri News, Sports

Advances in plan for individual gene therapies for leading cause of blindness Scientists use stem cells to investigate causes of degenerative eye disease Two patients with retinitis pigmentosa had mutations in a certain gene New gene therapy was used to rescue vision of mice with the same condition

By Julian Robinson

Published: 06:49 EST, 11 July 2014 | Updated: 08:08 EST, 11 July 2014

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Scientists have moved closer to a breakthrough in 'personalised' treatments for a leading cause of blindness.

Researchers have stepped up their bid to create individual gene therapies for one of the factors that triggers inherited vision loss.

They used 'induced' stem cells - taken from ordinary skin cells - to investigate patient-specific causes of the degenerative eye disease retinitis pigmentosa (RP), which leads to blindness or severe visual impairment.

Scientists have moved closer to a breakthrough in 'personalised' treatments for a leading cause of blindness

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Breakthrough in bid to cure blindness as scientists identify gene