University Times

RESEARCH NOTES

First in vivo gene therapy done here for hemophilia A

A 50-year-old man with hemophilia A received the first in vivo gene therapy for this disease on June 1, as part of a UPMC Health System clinical trial.

The trial, designed and initiated through Chiron Corp., uses Chiron's gene therapy introducing the blood-clotting protein called factor VIII. The therapy offers promise for the tens of thousands of men affected with this disease worldwide.

"We are very excited to participate in this study, which could permanently restore the ability to produce the clotting factor deficient in men with hemophilia A," said Margaret V. Ragni, Pitt professor of medicine, who is also the director of the Hemophilia Treatment Center of Western Pennsylvania and a member of the Medical and Scientific Advisory Committee of the National Hemophilia Foundation.

This small-scale, phase I trial is designed primarily to ensure the safety of the therapy and to determine the best dose of the factor VIII gene. Physicians also will measure the expression of the factor VIII gene in patients. Patients will be monitored closely for one year after treatment. Subsequently, they will be enrolled in a long-term surveillance registry.

Hemophilia A is a bleeding disorder that is transmitted genetically so that it affects only males. Approximately 1 in 10,000 men has the disorder. Affected individuals carry a defect in the gene for the factor VIII protein, which helps to clot blood.

As a consequence, they cannot produce functional factor VIII and may frequently suffer bleeding episodes, some of them life threatening. These episodes often occur in joints or other body cavities. Recurrent bleeding into joints may lead to chronic arthritis and pain.

Although patients infuse the factor VIII protein to prevent such episodes, this prophylactic therapy is costly and difficult to administer. Moreover, hemophiliacs may develop antibodies to the factor VIII protein.

The in vivo gene therapy, in contrast, offers the possibility of a long-term treatment by supplying a functional copy of the factor VIII gene to the body.

The therapy employs a retrovirus that has been modified so that it cannot replicate. Such replication-defective viruses have been used extensively in trials of clinical gene therapies for a variety of diseases. The gene for factor VIII is placed inside this vector, which patients receive directly as an infusion.

This approach differs considerably from a recently initiated trial of ex vivo gene therapy for hemophilia A, in which cells are taken from a patient, grown in culture, genetically modified and returned to the patient. Ex vivo gene therapies take longer to perform and must be tailored to each patient.

Once inside the body, scientists believe that the in vivo-introduced retrovirus delivers its genetic payload principally to the liver and spleen.

Researchers expect that the factor VIII gene will permanently integrate into a cell's genetic material and, in effect, becomes a drug-production factory. Normally, the liver manufactures the factor VIII protein.

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Windows of opportunity exist to stop pregnant teens' smoking

Concern for their unborn babies may inspire pregnant teens who smoke to quit, according to a report by a group of Pitt nurse researchers.

This creates a window of opportunity for health care providers to offer advice on stopping smoking, says the article, published in the June issue of the Journal of Pediatric Nursing.

"This window of opportunity occurs when we, as health care providers, can establish the fact that these teens are not just caring for themselves anymore," said Susan Albrecht, assistant professor. Smoking during pregnancy can result in low birth weight, growth retardation and other problems.

Pitt studies have found that multi-session smoking cessation programs with peer support have encouraged many pregnant teens to quit smoking. One-to-one peer support, group affiliation, peer role-modeling and adult support have been the most successful strategies with this population, according to Albrecht.

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Gene therapy could treat diabetic incontinence

UPMC researchers have controlled incontinence in an animal model of diabetes using a modified herpes virus to shuttle a therapeutic gene into damaged bladder nerves.

The results demonstrate the feasibility of this approach in humans. The findings were presented at a meeting of the American Society of Gene Therapy.

"This study provides the first evidence that we can repair visceral nerves and improve bladder function," said William Goins, Pitt assistant professor of molecular genetics and biochemistry.

Diabetes causes a number of complications, including damage to sensory nerves. Lacking sensory nerve input to the bladder, someone with diabetes cannot sense when it's time to urinate. Urine backs up, causing the bladder to enlarge. The swollen bladder, which often becomes infected, is treatable only with catheterization.

Because those with diabetes do not have a sufficient amount of a substance called nerve growth factor (NGF), which heals injured nerve cells, UPMC researchers surmised that delivery of the gene for NGF could provide a potential treatment.

The UPMC team capitalized on herpes' natural ability to infect nerve cells. They placed the gene for NGF inside a herpes vector modified to be harmless, then injected the NGF gene-bearing herpes vector into the bladders of rats with experimentally induced diabetes. Another group of diabetic rats received the herpes vector alone.

Ten weeks later, the diabetic rats that received the herpes vector with the NGF gene voided small amounts of fluid each time they urinated and had bladders half the size of control diabetic mice, which released large volumes of urine each time.

"This evidence really suggests that the introduced NGF gene effectively repairs the bladder nerve. If we can reproduce these results in diabetic people, we possibly could prevent many disease complications," said Goins.

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Brain blood flow mapping, measurement studies begin

Researchers in UPMC's department of neurological surgery are beginning two studies of people with partially and completely blocked blood vessels in the neck to determine the best methods to predict availability of brain blood flow.

Impaired blood flow to the brain may be a contributing factor in strokes. People with a completely blocked or a partially blocked neck artery may have brief attacks causing temporary blindness, numbness or weakness. These are individuals believed to be most at risk for a future stroke.

"Although the role of blood clots in causing strokes is well-known, the role of impaired blood flow is less clearly defined in part because of difficulties in measuring cerebral blood flow and other physiologic variables," said Howard Yonas, chief of cerebrovascular surgery, and Peter Jannetta, professor and vice chair of neurological surgery.

In the study, three methods for determining blood supply will be compared: transcranial doppler ultrasonography (TCD,) which measures the speed of blood flow in large arteries; near infrared spectroscopy (NIRS), which measures the amount of oxygen consumption in the veins of the brain, and xenon with computed tomography (Xe/CT) which measures the amount of blood flow in the brain. Researchers hope to determine the least invasive test to identify patients who are having symptoms due to compromised blood flow. About 125 patients will be enrolled in the study.