Category Archives: Gene therapy

Matthew Porteus Definitive Stem Cell Gene Therapy for Child Health: Stanford Childx Conference
Matthew Porteus discusses correcting mutations that cause childhood genetic diseases at the inaugural Childx Conference, 2015. Childx is a dynamic, TED-style conference designed to inspire...

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Matthew Porteus Definitive Stem Cell & Gene Therapy for Child Health: Stanford Childx Conference - Video

New research published online in Blood, the Journal of the American Society of Hematology (ASH), reports that children with "bubble boy disease" who undergo gene therapy have fewer infections and hospitalizations than those receiving stem cells from a partially matched donor. The research is the first to compare outcomes among children with the rare immune disorder -- also known as X-linked severe combined immunodeficiency (SCID-X1) -- receiving the two therapeutic approaches.

Children with SCID-X1 are born with a genetic defect that prevents them from developing a normal immune system. Because they are prone to life-threatening infections, infants with SCID-X1 must be kept in a sterile, protective bubble and require extensive treatment for survival beyond infancy. Infants with SCID are most likely to survive if they receive a stem cell transplant from a fully matched donor -- typically a sibling -- a procedure that replaces an infant's diseased stem cells with healthy donor cells. Following a successful fully matched transplant, infants with SCID-X1 are able to produce their own immune cells for the first time.

In the absence of a fully matched stem cell donor, infants with SCID-X1 may receive a transplant from a partial, or "half-matched," donor -- typically their mother or father. They may also undergo gene therapy, a much different approach. Gene therapy for SCID-X1 involves extracting an infant's own bone marrow, using a virus to replace faulty genetic material with a correct copy, and then giving "corrected" bone marrow back to the patient. Half-matched stem cell transplant and gene therapy represent secondary treatment approaches for infants with SCID-X1. Until recently, researchers had not yet compared outcomes among children treated with each respective approach.

"Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1," said lead study author Fabien Touzot, MD, PhD, of Necker Children's Hospital in Paris. "To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants."

Dr. Touzot and colleagues studied the medical records of 27 children who received either partial-matched transplant (13) or gene therapy (14) for SCID-X1 at Necker Children's Hospital between 1999 and 2013. The children receiving half-matched transplants and the children receiving gene therapy had been followed for a median of six and 12 years, respectively.

The researchers compared immune, or T-cell, development among patients and also compared key clinical outcomes such as infections and hospitalization. Investigators observed that the 14 children in the gene therapy group developed healthy immune cells faster than the 13 children in the half-matched transplant group. In fact, in the first six months after therapy, T cell counts had reached normal values for age in more than three-fourths (78%) of the gene therapy patients, compared to roughly one-fourth (26%) of the transplant group. The more rapid growth of the immune system in gene therapy patients was also associated with faster resolution of some opportunistic infections (11 months in gene therapy group vs. 25.5 months in half-matched transplant group). These patients also had fewer infection-related hospitalizations (3 in gene therapy group vs. 15 in half-matched transplant group).

"Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant," Dr. Touzot said. "These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach."

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The above story is based on materials provided by American Society of Hematology. Note: Materials may be edited for content and length.

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Gene therapy superior to half-matched transplant for 'bubble boy disease'

Research first to compare alternative approaches to fully matched transplant for rare immune disorder

(WASHINGTON - April 13, 2015) - New research published online today in Blood, the Journal of the American Society of Hematology (ASH), reports that children with "bubble boy disease" who undergo gene therapy have fewer infections and hospitalizations than those receiving stem cells from a partially matched donor. The research is the first to compare outcomes among children with the rare immune disorder - also known as X-linked severe combined immunodeficiency (SCID-X1) - receiving the two therapeutic approaches.

Children with SCID-X1 are born with a genetic defect that prevents them from developing a normal immune system. Because they are prone to life-threatening infections, infants with SCID-X1 must be kept in a sterile, protective bubble and require extensive treatment for survival beyond infancy. Infants with SCID are most likely to survive if they receive a stem cell transplant from a fully matched donor - typically a sibling - a procedure that replaces an infant's diseased stem cells with healthy donor cells. Following a successful fully matched transplant, infants with SCID-X1 are able to produce their own immune cells for the first time.

In the absence of a fully matched stem cell donor, infants with SCID-X1 may receive a transplant from a partial, or "half-matched," donor - typically their mother or father. They may also undergo gene therapy, a much different approach. Gene therapy for SCID-X1 involves extracting an infant's own bone marrow, using a virus to replace faulty genetic material with a correct copy, and then giving "corrected" bone marrow back to the patient. Half-matched stem cell transplant and gene therapy represent secondary treatment approaches for infants with SCID-X1. Until recently, researchers had not yet compared outcomes among children treated with each respective approach.

"Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1," said lead study author Fabien Touzot, MD, PhD, of Necker Children's Hospital in Paris. "To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants."

Dr. Touzot and colleagues studied the medical records of 27 children who received either partial-matched transplant (13) or gene therapy (14) for SCID-X1 at Necker Children's Hospital between 1999 and 2013. The children receiving half-matched transplants and the children receiving gene therapy had been followed for a median of six and 12 years, respectively.

The researchers compared immune, or T-cell, development among patients and also compared key clinical outcomes such as infections and hospitalization. Investigators observed that the 14 children in the gene therapy group developed healthy immune cells faster than the 13 children in the half-matched transplant group. In fact, in the first six months after therapy, T cell counts had reached normal values for age in more than three-fourths (78%) of the gene therapy patients, compared to roughly one-fourth (26%) of the transplant group. The more rapid growth of the immune system in gene therapy patients was also associated with faster resolution of some opportunistic infections (11 months in gene therapy group vs. 25.5 months in half-matched transplant group). These patients also had fewer infection-related hospitalizations (3 in gene therapy group vs. 15 in half-matched transplant group).

"Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant," Dr. Touzot said. "These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach."

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Blood, the most cited peer-reviewed publication in the field of hematology, is available weekly in print and online. Blood is the official journal of the American Society of Hematology (ASH), the world's largest professional society concerned with the causes and treatment of blood disorders.

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Study: Gene therapy superior to half-matched transplant for 'bubble boy disease'

From left: Tushar Menon, Inder Verma and Amy Firth. Salk Institute

From left: Tushar Menon, Inder Verma and Amy Firth. / Salk Institute

Those born with the immune disorder SCID-X1, or "bubble boy disease" may one day benefit from a new treatment to give them a functioning immune system, if new research from the Salk Institute succeeds.

Working with cultures of induced pluripotent stem cells from a patient, Salk scientists led by gene therapy expert Inder Verma repaired the genetic defect that causes the disease. Infants born with this inherited condition have virtually no immune resistance, and can be killed by infections easily defeated by normal immune systems.

Researchers were able to generate what appear to be mature NK, or "natural killer" immune cells, the first time this has been done. They also generated progenitors of T cells. This doesn't repair all the immune system, but it's a big step in that direction.

These preliminary results may pave the way to an alternative from treating these patients, Verma said. At present, patients can be treated with bone marrow transplants, but matching donors are hard to find. Gene therapy using a viral vector to repair the defect has been successful, but has caused leukemia in some patients when the corrective gene went into the wrong place. Newer forms of this therapy appear to have reduced the risk, but long-term followups of those treated are still in progress.

Salk researchers dispensed with viruses entirely by using the TALEN technology, which allows genetic editing without viruses, and is also more precise.

The study was published in the journal Cell Stem Cell on March 12. Tushar Menon and Amy L. Firth are the first authors. Verma is the senior author.

SCID-X1 is caused by an inactivating mutation on a gene called IL-2Rg located on the X chromosome, which means it exclusively affects males. (For females who carry the mutation on one chromosome, the functional gene on the other chromosome suffices).

One-letter mutation

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'Bubble boy' progress reported

Walking barefoot on sand "felt like walking on glass" for Keith Wenckowski, who has lived with type-one diabetes for more than two decades.

One of the participants in a new Northwestern Medicine study who suffered from painful diabetic neuropathy (PDN), Wenckowski finally found relief from the constant foot pain that required him to wear shoes at all times, even to the beach.

The study found that those with PDN who received two low dose rounds of a non-viral gene therapy called VM202 had significant improvement of their pain that lasted for months.

"I can now go to a beach and walk on the sand without feeling like I am walking on glass," Wenckowski said.

The results of this phase two, double-blind, placebo-controlled study will be published March 5 in the journal Annals of Clinical and Translation Neurology.

Right now there is no treatment for this disease of the peripheral nerves that affects 20 to 25 percent of diabetics. Patients with the most extreme form of the disease feel intense pain with a slight graze or touch. The pain can interfere with daily activities, sleep, mood and can diminish quality of life.

"Those who received the therapy reported more than a 50 percent reduction in their symptoms and virtually no side effects," said Dr. Jack Kessler, lead author of the study. "Not only did it improve their pain, it also improved their ability to perceive a very, very light touch."

Kessler is the Ken and Ruth Davee Professor of Stem Cell Biology in the department of neurology and a professor in the department of pharmacology at Northwestern University Feinberg School of Medicine. He also is an attending physician at Northwestern Memorial Hospital.

VM202 contains human hepatocyte growth factor (HGF) gene. Growth factor is a naturally occurring protein in the body that acts on cells -- in this case nerve cells -- to keep them alive, healthy and functioning. Future study is needed to investigate if the therapy can actually regenerate damaged nerves, reversing the neuropathy.

Wenckowski had continuous numbness, but now, more than a year since he received the therapy, his symptoms have not returned. "I am hoping the effects I am feeling do not cease," he said.

The rest is here:
Neuropathy: Relief for diabetics with painful condition

Advances in gene therapy and the deepening understanding of cancer will see the oft-fatal disease becoming treatable in two decades, said cancer researcher Inder M. Varma.

Cancer mutations are being exposed cancer is in retreat through a combination of surgery, radiation, chemotherapy, molecular and genetic therapy, cancer will become a chronic disease rather than a terminal one, said Dr. Verma, a professor in Laboratory of Genetics at the Salk Institute for Biological Studies, at the Infosys Science Foundation Lecture at the National Centre for Biological Sciences here on Wednesday.

His optimism was elaborated through an intriguing cat-and-mouse game that played out for over five years of research into the Glioblastomas multiforme (GBM), a lethal form of brain cancer that kills the patient within 14 months.

Understanding GBM was critical as relapse, even after surgery or treatment, was certainty, said Prof. Verma.

The researchers at the Salk Institute developed a novel genetic technique to switch on genes in around five cells of a mouse brain to make them into cancer cells. The cells grew to all parts of the brain, but more importantly, they started to exhibit stem cell characteristics, said Dr. Verma.

Unlike the normal cell, a stem cell can divide into specialised cells a phenomenon that explains the resurgent ability of the GBM cancer. Even if you surgically remove the tumour, one cell is enough to recreate the cancer again, he explained.

Using gene therapy, the team of scientists attempted to block this ability as well as use drugs to block blood supply to the cancer cell. While the tumour did become smaller, it became even more invasive. Though the treatment did not work, the cancer cell did reveal the genes responsible for its invasiveness.

We began to genetically cut out the cancers invasiveness, and for the first time, experiments showed GBM cancer could be controlled This is an exciting area that can be possibly used to treat other forms of cancer, said Dr. Verma.

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Cancer set to become treatable: expert

Dr. Theodore Friedmann is a longtime faculty member at UC San Diego and a pioneer in gene therapy. / photo by Nelvin C. Cepeda * U-T San Diego

Dr. Theodore Friedmann, a pioneer in the booming field of gene therapy, has been named a 2015 winner of the prestigious Japan Prize.

A pediatrician-turned-researcher at UC San Diego, Friedmann is renowned for demonstrating in the lab that it is possible to correct a genetic defect by adding a functional gene to defective cells, a feat he and colleagues accomplished in 1968. Since then, Friedmann has been guiding the young science through controversies, ethical challenges and setbacks.

Friedmann shares the prize in "medical science and medicinal science" with Dr. Alain Fischer of the Necker Hospital in Paris, France. Fischer helped demonstrate gene therapy's clinical ability to treat a genetic immune deficiency that makes patients extremely vulnerable to infections.

Along with the recognition, Friedmann and Fischer will split a $416,600 award, a certificate and gold medal. There's also the prospect of future recognition: several Japan Prize winners have gone on to win the Nobel Prize.

Friedmann is known not only as a scientist who demonstrated gene therapy is possible, but as a thinker who has dampened the waves of excessive exuberance and despondency that often accompanies the passage of research discoveries into therapies. He has also cautioned his fellow scientists to approach gene therapy with great caution.

In 1972, Friedmann co-authored an influential article in the journal Science, "Gene therapy for human genetic disease?" proposing a program of research advancement and safety precautions with an eye to eventual therapy. In February, 2010, he coauthored an article in Science about the potential use of performance-enhancing "gene doping" in sports.

Those who didn't heed Friedmann's warnings ran into trouble. For example, in 1999 gene therapy patient Jesse Gelsinger, 18, died due to an immune reaction. Gelsinger had a mild form of a genetically caused liver disease, controlled with drugs and diet. He was enrolled to test a treatment to be used in babies with a fatal form of the disease. But Gelsinger himself had little to gain.

A mountain of bad publicity threatened to sink the field. The New York Times wrote about "The Biotech Death of Jesse Gelsinger." As a consequence, other new forms of therapy, such as stem cell treatments, have progressed more slowly to avoid a repeat.

The Gelsinger disaster has receded into the background, as safer forms of gene therapy edge closer to becoming an accepted part of medicine. Forms of gene therapy are now being tested in clinical trials to treat such different diseases as cancer, sickle cell anemia and HIV, with impressive results.

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Friedmann wins Japan Prize for gene therapy

Sacramento, Calif. (PRWEB) December 22, 2014

Using modified human stem cells, a team of UC Davis scientists has developed an improved gene therapy strategy that in animal models shows promise as a functional cure for the human immunodeficiency virus (HIV) that causes AIDS. The achievement, which involves an improved technique to purify populations of HIV-resistant stem cells, opens the door for human clinical trials that were recently approved by the U.S. Food and Drug Administration.

We have devised a gene therapy strategy to generate an HIV-resistant immune system in patients, said Joseph Anderson, principal investigator of the study and assistant professor of internal medicine. We are now poised to evaluate the effectiveness of this therapy in human clinical trials.

Anderson and his colleagues modified human stem cells with genes that resist HIV infection and then transplanted a near-purified population of these cells into immunodeficient mice. The mice subsequently resisted HIV infection, maintaining signs of a healthy immune system.

The findings are now online in a paper titled Safety and efficacy of a tCD25 pre-selective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells, and will be published in the journal Stem Cells.

Using a viral vector, the researchers inserted three different genes that confer HIV resistance into the genome of human hematopoietic stem cells cells destined to develop into immune cells in the body. The vector also contains a gene which tags the surface of the HIV-resistant stem cells. This allows the gene-modified stem cells to be purified so that only the ones resistant to HIV infection are transplanted. The stem cells were then delivered into the animal models, with the genetically engineered human stem cells generating an HIV-resistant immune system in the mice.

The three HIV-resistant genes act on different aspects of HIV infection one prevents HIV from exposing its genetic material when inside a human cell; another prevents HIV from attaching to target cells; and the third eliminates the function of a viral protein critical for HIV gene expression. In combination, the genes protect against different HIV strains and provide defense against HIV as it mutates.

After exposure to HIV infection, the mice given the bioengineered cells avoided two important hallmarks of HIV infection: a drop in human CD4+ cell levels and a rise in HIV virus in the blood. CD4+ is a glycoprotein found on the surface of white blood cells, which are an important part of the normal immune system. CD4+ cells in patients with HIV infection are carefully monitored by physicians so that therapies can be adjusted to keep them at normal level: If levels are too low, patients become susceptible to opportunistic infections characteristic of AIDS. In the experiments, mice that received the genetically engineered stem cells and infected with two different strains of HIV were still able to maintain normal CD4+ levels. The mice also showed no evidence of HIV virus in their blood.

Although other HIV investigators had previously bioengineered stem cells to be resistant to HIV and conducted clinical trials in human patients, efforts were stymied by technical problems in developing a pure population of the modified cells to be transplanted into patients. During the process of genetic engineering, a significant percentage of stem cells remain unmodified, leading to poor resistance when the entire population of modified cells is transplanted into humans or animal models. In the current investigation, the UC Davis team introduced a handle onto the surface of the bioengineered cells so that the cells could be recognized and selected. This development achieved a population of HIV-resistant stem cells that was greater than 94 percent pure.

Developing a technique to purify the population of HIV-resistant stem cells is the most important breakthrough of this research, said Anderson, whose laboratory is based at the UC Davis Institute for Regenerative Cures. We now have a strategy that shows great promise for offering a functional cure for the disease.

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New Technique for Bioengineering Stem Cells Shows Promise in HIV Resistance

Scientists at Indiana University and colleagues at Stanford and the University of Texas have demonstrated a technique for "editing" the genome in sperm-producing adult stem cells, a result with powerful potential for basic research and for gene therapy.

The researchers completed a "proof of concept" experiment in which they created a break in the DNA strands of a mutant gene in mouse cells, then repaired the DNA through a process called homologous recombination, replacing flawed segments with correct ones.

The study involved spermatogonial stem cells, which are the foundation for the production of sperm and are the only adult stem cells that contribute genetic information to the next generation. Repairing flaws in the cells could thus prevent mutations from being passed to future generations.

"We showed a way to introduce genetic material into spermatogonial stem cells that was greatly improved from what had been previously demonstrated," said Christina Dann, associate scientist in the Department of Chemistry at IU Bloomington and a co-author of the study. "This technique corrects the mutation, theoretically leaving no other mark on the genome."

The paper, "Genome Editing in Mouse Spermatogonial Stem/Progenitor Cells Using Engineered Nucleases," was published in the online science journal PLOS-ONE.

The lead author, Danielle Fanslow, carried out the research as an IU research associate and is now a doctoral student at Northwestern University. Additional co-authors are from the Stanford School of Medicine and the University of Texas Southwestern Medical Center.

A challenge to the research was the fact that spermatogonial stem cells, like many types of adult stem cells, are notoriously difficult to isolate, culture and work with. It took years of intensive effort by multiple laboratories before conditions were created a decade ago to maintain and propagate the cells.

For the IU research, a primary hurdle was to find a way to make specific, targeted modifications to the mutant mouse gene without the risk of disease caused by random introduction of genetic material. The researchers used specially designed enzymes, called zinc finger nucleases and transcription activator-like effector nucleases, to create a double strand break in the DNA and bring about the repair of the gene.

Stem cells that had been modified in the lab were then transplanted into the testes of sterile mice. The transplanted cells grew or colonized within the mouse testes, indicating the stem cells were viable. However, attempts to breed the mice were not successful.

"Whether the failure to produce sperm was a result of abnormalities in the transplanted cells or the recipient testes was unclear," the researchers write.

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'Genome editing' could correct genetic mutations for future generations

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Newswise Study results of CD19-directed chimeric antigen receptor (CAR) therapy using the Sleeping Beauty non-viral transduction system to modify T cells has demonstrated further promise in patients with advanced hematologic malignancies.

Patients who had acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) were part of clinical trials at The University of Texas MD Anderson Cancer Center, which used the Sleeping Beauty gene transfer system initially discovered at the University of Minnesota.

Results from the study were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) annual conference in San Francisco and were published in the Dec. 5 issue of the ASH journal Blood.

The Sleeping Beauty gene was named for its ability to awaken an extinct transposon DNA that can replicate itself and insert the copy back into the genome. This allows a gene to be transferred into a DNA molecule known as a plasmid. An enzyme called a transposase binds to the plasmid, cuts the transposon and gene out of the plasmid and pastes it into the target DNA sequence. This gene transfer system was the basis for the MD Anderson clinical trials.

Using the Sleeping Beauty gene transfer system, Laurence Cooper, M.D., Ph.D., professor of pediatrics and Partow Kebriaei, M.D., associate professor of stem cell transplantation and cellular therapy, were able to plug a gene into T cells, creating an artificial or chimeric antigen receptor (CAR) on the T cell that recognizes and binds to CD19, a cell surface on B cells. The resultant product known as CAR T cells are produced at MD Anderson and are being employed in the Sleeping Beauty clinical trials.

We are treating patients with advanced CD19 positive hematologic malignancies using CAR T cells in combination with conventional blood stem cell transplantation, said Kebriaei. We are also treating patients who had active disease but had not received blood stem cell transplantation.

Patients were recipients of autologous (patients own cells) or allogeneic (donor cells) stem cell transplantations, which were administered in combination with CAR. Kebriaei reported no acute or long-term toxicity in the 33 patients treated.

Five patients at high risk for relapse were treated with CAR T cells along with autologous stem cell transplant, and four of those patients remain in complete remission with a median follow-up of 12 months, she said. Among 13 patients treated with donor CAR T cells after allogeneic stem cell transplantation, six remain in complete remission with a median follow-up of 7.5 months.

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Experimental Gene Therapy Successful in Certain Lymphomas and Leukemia