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Gene therapy using part of HIV virus treats two rare childhood diseases

Scientists have developed a genetic therapy to treat two rare childhood diseases using a component of the HIV virus.

The research, which was detailed in two studies published in Science on June 11, showed that scientists were able to use an HIV virus vector -- which acts as a tool to help put genetic material into cells -- on three children with metachromatic leukodystrophy and three others with Wiskott-Aldrich syndrome. Their diseases have stopped progressing and some of the patients have stopped showing symptoms for 18 to 32 months following the therapy.

Using a vector of the virus, the mechanism in which it gets into cells, is not the same as giving the children the actual HIV virus.

"Three years after the start of the clinical trial, the results obtained from the first six patients are very encouraging. The therapy is not only safe, but also effective and able to change the clinical history of these severe diseases," author Luigi Naldini, a researcher from the San Raffaele Telethon Institute for Gene Therapy, said in a press release.

Metachromatic leukodystrophy is an inherited genetic mutation that causes fats called sulfatides to collect in cells, especially in those that produce a substance that surrounds and protects nerves, called myelin. In patients with the disorder, the sulfatide collection ends up destroying the white matter that makes up part of the nervous system. This affects the brain, spinal chord and sensory cells that registered touch, pain, heat and sound.

Eventually the patients no longer have cognitive functions or motor skills, and they cannot feel different sensations. Other symptoms include seizures, paralysis, inability to speak, blindness, hearing loss and eventually loss of awareness. There is currently no cure.

About one out of 40,000 to 160,000 people worldwide have the disorder, the National Institutes of Health reports. The most common form of the condition, called late infantile form, affects 50 to 60 percent of people with the disorder starting at about 2 years old. Twenty to 30 percent of patients will have a juvenile form which begins to manifest around the age of 4 through adolescence. The adult form affects 15 to 20 percent of patients with metachromatic leukodystrophy, and starts appearing during teenage years or later.

People with Wiskott-Aldrich syndrome do not have a normal immune system and have a harder time creating blood clots. The disease, which is caused by an inherited genetic mutation on the X chromosome, causes abnormal or nonfunctional white blood cells, which puts the patients at risk of immune and inflammatory disorders.

The condition is typically found in males, and has an incidence of 1 to 10 cases per one million males, the NIH said. It is rarely found in women. Wiskott-Aldrich can be treated if the patients receive a bone marrow or stem cell transplant, which can work very well if the donation is a close match.

The researchers used an HIV virus vector to insert a corrected form of defective genes at the root of these diseases into the patients' own blood stem cells. Then, the healthy blood stem cells were surgically implanted in to the subject.

For the patients with Wiskott-Aldrich syndrome, the implanted stem cells work by replacing the person's defective blood cells for the corrected cells. Eventually the subjects were able to have correctly functioning immune systems and white blood cells.

"Thanks to gene therapy, the children no longer have to face severe bleeding and infection. They can run, play and go to school," co-author Alessandro Aiuti, head of research of the Pediatric Clinic at TIGET and coordinator of the clinical study on the Wiskott-Aldrich, said in a press release.

However, for metachromatic leukodystrophy, the process is a little more complicated. The corrected stem cells entered the brain and released a correct protein. The the cells collected the protein instead of the sulfatide fat.

"The winning card was to make engineered cells able to produce a quantity of protein much higher than normal, and thus effectively counteract the neurodegenerative process," co-author Alessandra Biffi, a researcher at the Pediatric Clinic at TIGET who led the metachromatic leukodystrophy portion of the study, said in a press release.

A similar method had been used in the past, but was shown to increase the chance of blood-related cancers especially in patients with Wiskott-Aldrich syndrome. However, scientists believed the virus was putting the corrected genes next to a gene that was likely to cause cancer, which increased the chance the person would develop the disease.

This time, the researchers were able to reduce the risk of the corrected gene inserting itself next to the cancer-activating one. They still have to track the patients for much longer and need more patient trials, but for now the researchers are hopeful.

"Until now we have never seen a way to engineer stem cells using gene therapy that is as effective and safe as this one," Eugenio Monti, a researcher at the Pediatric Clinic at TIGET who coordinated the molecular analysis of patients' cells, said in a press release. "These results pave the way for new therapies for other more common diseases."