Category Archives: Gene therapy

A treatment for Cystic Fibrosis. A cure for AIDS. The end of cancer. That's what the newspapers promised us in the early 1990's. Gene therapy was the answer to what ailed us. Scientists had at last learned how to insert healthy genes into unhealthy people. And those healthy genes would either replace the bad genes causing diseases like CF, sickle-cell anemia and hemophilia or stimulate the body's own immune system to rid itself of HIV and some forms of cancer. A decade later, none of these treatments have come to fruition and research into gene therapy has become politically unpopular, making clinical trials hard to approve and research dollars hard to come by. But some researchers who are taking a different approach to gene therapy could be on the road to more success than ever before. - - - - - - - - - - - -

Early Promise

Almost as soon as Watson and Crick unwound the double helix in the 1950's, researchers began considering the possibility- and ethics- of gene therapy. The goals were lofty- to fix inherited genetic diseases such as Cystic Fibrosis and hemophilia forever.

Gene therapists planned to isolate the relevant gene in question, prepare good copies of that gene, then deliver them to patients' cells. The hope was that the treated cells would give rise to new generations of healthy cells for the rest of the patient's life. The concept was elegant, but would require decades of research to locate the genes that cause illnesses.

By 1990, it was working in the lab. By inserting healthy genes into cells from CF patients, scientists were able to transmogrify the sick cells as if by magic into healthy cells.

That same year, four-year-old Ashanti DeSilva became the first person in history to receive gene therapy. Dr. W. French Anderson of the National Heart, Lung and Blood Institute and Dr. Michael Blaese and Dr. Kenneth Culver, both of the National Cancer Institute, performed the historic and controversial experiment.

DeSilva suffered from a rare immune disorder known as ADA deficiency that made her vulnerable to even the mildest infections. A single genetic defect- like a typo in a novel- left DeSilva unable to produce an important enzyme. Without that enzyme, DeSilva was likely to die a premature death.

Anderson, Blaese and Culver drew the girl's blood and treated her defective white blood cells with the gene she lacked. The altered cells were then injected back into the girl, where- the scientists hoped- they would produce the enzyme she needed as well as produce future generations of normal cells.

Though the treatment proved safe, its efficacy is still in question. The treated cells did produce the enzyme, but failed to give rise to healthy new cells. DeSilva, who is today relatively healthy, still receives periodic gene therapy to maintain the necessary levels of the enzyme in her blood. She also takes doses of the enzyme itself, in the form of a drug called PEG-ADA, which makes it difficult to tell how well the gene therapy would have worked alone.

"It was a very logical approach," says Dr. Jeffrey Isner, Chief of Vascular Medicine and Cardiovascular Research at St. Elizabeth's Medical Center in Boston as well as Professor of Medicine at Tufts University School of Medicine. "But in most cases the strategy failed, because the vectors we have today are not ready for prime time." - - - - - - - - - - - - 4 pages: | 1 | 2 | 3 | 4 |

Photo: Dr. W. French Anderson

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Gene therapy - PBS

Researchers are looking at different ways of using gene therapy, including

Some types of gene therapy aim to boost the body's natural ability to attack cancer cells. Our immune system has cells that recognise and kill harmful things that can cause disease, such as cancer cells.

There are many different types of immune cell. Some of them produce proteins that encourage other immune cells to destroy cancer cells. Some types of therapy add genes to a patient's immune cells to make them better at finding or destroying particular types of cancer. There are a few trials using this type of gene therapy in the UK.

Some gene therapies put genes into cancer cells to make the cells more sensitive to particular treatments such as chemotherapy or radiotherapy. This type of gene therapy aims to make the other cancer treatments work better.

Some types of gene therapy deliver genes into the cancer cells that allow the cells to change drugs from an inactive form to an active form. The inactive form of the drug is called a pro drug.

After giving the carrier containing the gene, the doctor gives the patient the pro drug. The pro drug may be a tablet or capsule that you swallow, or you may have it into the bloodstream.

The pro drug circulates in the body and doesn't harm normal cells. But when it reaches the cancer cells, the gene activates it and the drug kills the cancer cells.

Some gene therapies block processes that cancer cells use to survive. For example, most cells in the body are programmed to die if their DNA is damaged beyond repair. This is called programmed cell death or apoptosis. But cancer cells block this process so they don't die even when they are supposed to. Some gene therapy strategies aim to reverse this blockage. Doctors hope that these new types of treatment will make the cancer cells die.

Some viruses infect and kill cells. Researchers are working on ways to change these viruses so that they only target and kill cancer cells, leaving healthy cells alone. This sort of treatment uses the viruses to kill cancer cells directly rather than to deliver genes. So it is not cancer gene therapy in the true sense of the word. But doctors sometimes refer to it as gene therapy.

One example of this type of research uses the cold sore virus (herpes simplex virus). The changed virus is called Oncovex. It has been tested in early clinical trials for advanced melanoma, pancreatic cancer and head and neck cancers.

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Gene therapy | Cancer Research UK

Much of today's cancer research is devoted to finding missing or defective genes that cause cancer or increase an individual's risk for certain types of cancer. Gene research at MDAnderson has resulted in many important discoveries. We identified the mutated multiple advanced cancers gene (MMAC1) involved in some common cancers. We also performed the first successful correction of a defective tumor suppressor gene (p53) in human lung cancer. Current gene therapies are experimental, and many are still tested only on animals. There are some clinical trials involving a very small number of human subjects.

The potential benefits of gene therapy are two-fold:

The focus of most gene therapy research is the replacement of a missing or defective gene with a functional, healthy copy, which is delivered to target cells with a "vector." Viruses are commonly used as vectors because of their ability to penetrate a cells DNA. These vector viruses are inactivated so they cannot reproduce and cause disease. Gene transfer therapy can be done outside the body (ex vivo) by extracting bone marrow or blood from the patient and growing the cells in a laboratory. The corrected copy of the gene is introduced and allowed to penetrate the cells DNA before being injected back into the body. Gene transfers can also be done directly inside the patients body (in vivo).

Other therapies include:

Gene therapy is a complicated area of research, and many questions remain unanswered. Some cancers are caused by more than one gene, and some vectors, if used incorrectly, can actually cause cancer or other diseases. Replacing faulty genes with working copies also brings up ethical issues that must be addressed before these therapies can be accepted for preventing cancer. Talk to your cancer specialist about the implications of gene therapy.

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Types of Gene Therapy Treatment | MD Anderson Cancer Center

Researchers have been working for decades to bring gene therapy to the clinic, yet very few patients have received any effective gene-therapy treatments. But that doesn't mean gene therapy is an impossible dream. Even though gene therapy has been slow to reach patients, its future is very encouraging. Decades of research have taught us a lot about designing safe and effective vectors, targeting different types of cells, and managing and minimizing immune responses in patients. We've also learned a lot about the disease genes themselves. Today, many clinical trials are underway, where researchers are carefully testing treatments to ensure that any gene therapy brought into the clinic is both safe and effective.

Below are some gene therapy success stories. Successes represent a variety of approachesdifferent vectors, different target cell populations, and both in vivo and ex vivo approachesto treating a variety of disorders.

Sebastian Misztal was a patient in a hemophilia gene therapy trial in 2011. Following the treatment, Misztal no longer had spontaneous bleeding episodes. Credit: UCLH/UCL NIHR Biomedical Research Centre

Several inherited immune deficiencies have been treated successfully with gene therapy. Most commonly, blood stem cells are removed from patients, and retroviruses are used to deliver working copies of the defective genes. After the genes have been delivered, the stem cells are returned to the patient. Because the cells are treated outside the patient's body, the virus will infect and transfer the gene to only the desired target cells.

Severe Combined Immune Deficiency (SCID) was one of the first genetic disorders to be treated successfully with gene therapy, proving that the approach could work. However, the first clinical trials ended when the viral vector triggered leukemia (a type of blood cancer) in some patients. Since then, researchers have begun trials with new, safer viral vectors that are much less likely to cause cancer.

Adenosine deaminase (ADA) deficiency is another inherited immune disorder that has been successfully treated with gene therapy. In multiple small trials, patients' blood stem cells were removed, treated with a retroviral vector to deliver a functional copy of the ADA gene, and then returned to the patients. For the majority of patients in these trials, immune function improved to the point that they no longer needed injections of ADA enzyme. Importantly, none of them developed leukemia.

Gene therapies are being developed to treat several different types of inherited blindnessespecially degenerative forms, where patients gradually lose the light-sensing cells in their eyes. Encouraging results from animal models (especially mouse, rat, and dog) show that gene therapy has the potential to slow or even reverse vision loss.

The eye turns out to be a convenient compartment for gene therapy. The retina, on the inside of the eye, is both easy to access and partially protected from the immune system. And viruses can't move from the eye to other places in the body. Most gene-therapy vectors used in the eye are based on AAV (adeno-associated virus).

In one small trial of patients with a form of degenerative blindness called LCA (Leber congenital amaurosis), gene therapy greatly improved vision for at least a few years. However, the treatment did not stop the retina from continuing to degenerate. In another trial, 6 out of 9 patients with the degenerative disease choroideremia had improved vision after a virus was used to deliver a functional REP1 gene.

Credit: Jean Bennett, MD, PhD, Perelman School of Medicine, University of Pennsylvania; Manzar Ashtari, Ph.D., of The Children's Hospital of Philadelphia, Science Translational Medicine.

People with hemophilia are missing proteins that help their blood form clots. Those with the most-severe forms of the disease can lose large amounts of blood through internal bleeding or even a minor cut.

In a small trial, researchers successfully used an adeno-associated viral vector to deliver a gene for Factor IX, the missing clotting protein, to liver cells. After treatment, most of the patients made at least some Factor IX, and they had fewer bleeding incidents.

Patients with beta-Thalassemia have a defect in the beta-globin gene, which codes for an oxygen-carrying protein in red blood cells. Because of the defective gene, patients don't have enough red blood cells to carry oxygen to all the body's tissues. Many who have this disorder depend on blood transfusions for survival.

In 2007, a patient received gene therapy for severe beta-Thalassemia. Blood stem cells were taken from his bone marrow and treated with a retrovirus to transfer a working copy of the beta-globin gene. The modified stem cells were returned to his body, where they gave rise to healthy red blood cells. Seven years after the procedure, he was still doing well without blood transfusions.

A similar approach could be used to treat patients with sickle cell disease.

In 2012, Glybera became the first viral gene-therapy treatment to be approved in Europe. The treatment uses an adeno-associated virus to deliver a working copy of the LPL (lipoprotein lipase) gene to muscle cells. The LPL gene codes for a protein that helps break down fats in the blood, preventing fat concentrations from rising to toxic levels.

Several promising gene-therapy treatments are under development for cancer. One, a modified version of the herpes simplex 1 virus (which normally causes cold sores) has been shown to be effective against melanoma (a skin cancer) that has spread throughout the body. The treatment, called T-VEC, uses a virus that has been modified so that it will (1) not cause cold sores; (2) kill only cancer cells, not healthy ones; and (3) make signals that attract the patient's own immune cells, helping them learn to recognize and fight cancer cells throughout the body. The virus is injected directly into the patient's tumors. It replicates (makes more of itself) inside the cancer cells until they burst, releasing more viruses that can infect additional cancer cells.

A completely different approach was used in a trial to treat 59 patients with leukemia, a type of blood cancer. The patients' own immune cells were removed and treated with a virus that genetically altered them to recognize a protein that sits on the surface of the cancer cells. After the immune cells were returned to the patients, 26 experienced complete remission.

Patients with Parkinson's disease gradually lose cells in the brain that produce the signaling molecule dopamine. As the disease advances, patients lose the ability to control their movements.

A small group of patients with advanced Parkinson's disease were treated with a retroviral vector to introduce three genes into cells in a small area of the brain. These genes gave cells that don't normally make dopamine the ability to do so. After treatment, all of the patients in the trial had improved muscle control.

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Gene Therapy Successes - Learn Genetics

An experimental gene therapy has improved eyesight in patients with a rare, inherited eye disease that can cause blindness, according to its developer, Spark Therapeutics Inc.

The company said it plans to apply to the Food and Drug Administration next year for approval to market the treatment. If accepted, this would be the first gene therapy to win approval in the United States.

"We saw substantial restoration of vision in patients who were progressing toward complete blindness," Dr. Albert M. Maguire, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania, said in a statement.

There were no serious adverse effects associated with the treatment, the company reported.

The news comes about a week after a hospital in the U.K. announced it had performed a pioneering human embryonic stem cell operation on a patient with the aim of curing a different, more common cause of blindness known as macular degeneration.

Gene therapy involves injecting genetic material into a person's cells to treat or prevent a disease. While research in this area has been going on since the late 1990's, no such treatment has been approved in the U.S. The European Commission approved the Western world's first gene therapy in 2012 for an extremely rare disease in patients with a particular enzyme deficiency.

Spark's treatment, called SPK-RPE65, is targeted at mutations in a gene called RPE65, which plays a role in maintaining the health of the photoreceptors in the eye. The condition can progress to complete blindness.

The Phase III trial included a total of 31 participants, 21 of whom were given the treatment and 10 of whom weren't. Researchers evaluated the participants at multiple points over the course of a year for their performance in navigating a mobility course under a variety of light levels. These levels ranged from the equivalent of a "moonless summer night" to a brightly lit office, according to the statement.

"The majority of the subjects given SPK-RPE65 derived the maximum possible benefit that we could measure on the primary visual function test, and this impressive effect was confirmed by a parallel improvement in retinal sensitivity," Maguire said. "If approved, SPK-RPE65 should have a positive, meaningful impact on the lives of patients with this debilitating condition."

But much still remains unknown at this time. Spark has not yet made the actual trial data public, and it is unclear what it will take for the FDA to approve the treatment. The company said it plans to present additional data from the trial in a series of scientific meetings in the coming months.

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Gene therapy for rare cause of blindness shows promise ...

Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they cant cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patients cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

The Genetic Science Learning Center at the University of Utah provides information about various technical aspects of gene therapy in Gene Delivery: Tools of the Trade. They also discuss other approaches to gene therapy and offer a related learning activity called Space Doctor.

The Better Health Channel from the State Government of Victoria (Australia) provides a brief introduction to gene therapy, including the gene therapy process and delivery techniques.

Penn Medicines Oncolink describes how gene therapy works and how it is administered to patients.

Next: Is gene therapy safe?

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Genetics Home Reference: How Does Gene Therapy Work?

Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they cant cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patients cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

The Genetic Science Learning Center at the University of Utah provides information about various technical aspects of gene therapy in Gene Delivery: Tools of the Trade. They also discuss other approaches to gene therapy and offer a related learning activity called Space Doctor.

The Better Health Channel from the State Government of Victoria (Australia) provides a brief introduction to gene therapy, including the gene therapy process and delivery techniques.

Penn Medicines Oncolink describes how gene therapy works and how it is administered to patients.

Next: Is gene therapy safe?

Continued here:
How does gene therapy work? - Genetics Home Reference

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Gene Therapy

Challenges in Gene Therapy?

Gene therapy is not a new field; it has been evolving for decades. Despite the best efforts of researchers around the world, however, gene therapy has seen only limited success. Why?

Gene therapy poses one of the greatest technical challenges in modern medicine. It is very hard to introduce new genes into cells of the body and keep them working. And there are financial concerns: Can a company profit from developing a gene therapy to treat a rare disorder? If not, who will develop and pay for these life-saving treatments?

Let's look at some of the main challenges in gene therapy.

For some disorders, gene therapy will work only if we can deliver a normal gene to a large number of cellssay several millionin a tissue. And they have to the correct cells, in the correct tissue. Once the gene reaches its destination, it must be activated, or turned on, to make the protein it encodes. And once it's turned on, it must remain on; cells have a habit of shutting down genes that are too active or exhibiting other unusual behaviors.

Introducing changes into the wrong cells Targeting a gene to the correct cells is crucial to the success of any gene therapy treatment. Just as important, though, is making sure that the gene is not incorporated into the wrong cells. Delivering a gene to the wrong tissue would be inefficient, and it could cause health problems for the patient.

For example, improper targeting could incorporate the therapeutic gene into a patient's germline, or reproductive cells, which ultimately produce sperm and eggs. Should this happen, the patient would pass the introduced gene to his or her children. The consequences would vary, depending on the gene.

Our immune systems are very good at fighting off intruders such as bacteria and viruses. Gene-delivery vectors must be able to avoid the body's natural surveillance system. An unwelcome immune response could cause serious illness or even death.

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Challenges in Gene Therapy - Learn Genetics

Sean Wu Definitive Stem Cell and Gene Therapy for Child Health: Stanford Childx Conference
Sean Wu discusses his work engineering stem cells to cure heart disease at the inaugural Childx Conference, 2015. Childx is a dynamic, TED-style conference designed to inspire innovation that...

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Sean Wu Definitive Stem Cell and Gene Therapy for Child Health: Stanford Childx Conference - Video

Hiro Nakauchi Definitive and Stem Cell Gene Therapy for Child Health: Stanford Childx Conference
Hiro Nakauchi discusses new stem cell therapies at the inaugural Childx Conference, 2015. Childx is a dynamic, TED-style conference designed to inspire innovation that improves pediatric and...

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Hiro Nakauchi Definitive and Stem Cell & Gene Therapy for Child Health: Stanford Childx Conference - Video