AIDS Virus Modified, Used To Deliver Gene Therapy To Rare Disease Patients

Scientists have used a modified AIDS virus to successfully treat six children suffering from rare inherited genetic diseases.

By disabling HIV’s ability to replicate and run rampant in a patient’s body, scientists can then safely use the virus as a courier for gene therapy. Blood stem cells are taken from a patient with a genetic disorder and infected with a virus carrying the non-mutated version of the gene, which inserts it into the cells’ DNA. Then, the patient gets their own modified blood cells back.

In a pair of papers published in the journal Science on Thursday, an international team of researchers led by the San Rafaele Telethon Institute for Gene Therapy (TIGET) in Italy reported on their success with the technique in three children with metachromatic leukodystrophy, and three with the rare disease Wiskott-Aldrich Syndrome. The trials began in the spring of 2010, and three years later, all six children are doing well.

“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,” senior author Luigi Naldini, the director of TIGET, said in a statement. “After 15 years of effort and our successes in the laboratory, but frustration as well, it's really exciting to be able to give a concrete solution to the first patients.”

The new technique also seems to be safer than a similar treatment that uses a different class of virus to deliver gene therapy.

“We’re taking advantage of what we’ve learned over the past 30-some-odd years about this family of viruses,” Baylor College of Medicine pediatrician and immunologist Jordan Orange, a co-author on one of the papers published Thursday, said in a phone interview. “Clearly the clinical side of this is incredibly exciting.”

Metachromatic leukodystrophy impairs the development of the myelin sheath, a fatty covering that insulates nerve fibers. At birth, the children appear healthy, but their nervous systems start to degrade quickly. Most children with MLD die by 5 years old, and there are currently no other treatments available.

Children with Wiskott-Aldrich Syndrome have a mutation that affects tiny protein filaments that provide internal structure to a person’s cells as part of a scaffold called the cytoskeleton. The cell is constantly tearing down and rebuilding its internal structure as it grows, moves and duplicates, so being able to effectively rebuild the cytoskeleton is essential to a person’s daily function. The filaments affected by the disease, which alters a key protein called WASP, are analogous to the metal girders that support buildings.

Basically, “what’s wrong in this disease is you can’t make new ‘girders’ real well,” Orange says. “The cell is unable to organize its insides.”

Because of this impaired cellular functioning, Wiskott-Aldrich patients have a compromised immune system that leaves them much more vulnerable to diseases, cancers and infections. Patients also tend to bleed easily, thanks to a defect in the platelets of their blood.

One of the three patients in the Science study is one of Orange’s charges. He saw the boy soon after his birth, and blood tests confirmed the patient had the more severe form of the disease. Sometimes this severe form can be treated with a bone marrow transplant – which has about a 75 percent cure rate – but in this boy’s particular case, there was no matching donor. Left untreated, the severe form of Wiskott-Aldrich is usually fatal by age 12.

Doctors have explored the possibility of using viruses to deliver the normal gene that encodes the WASP protein before. But previous methods using another kind of virus – sort of a “cousin” of HIV – sometimes resulted in patients developing blood cancers.

The problem with the other viral vector was that it would “only insert [itself] into places in DNA that are open and actively being used,” Orange says. “Those places are often the parts that maintain normal [cellular] growth. If you go in and plug something ahead of that, you can get uncontrolled growth.”

The modified HIV, which belongs to a genus of viruses called lentivirus, is much more varied in selecting where to insert itself, and as a result is much less likely to insert itself in a position that could end up causing cancer. When the scientists examined the patients after treatment, the difference caused by the takeup of the normal gene was striking.

“What I could see with my own eyes was that when the correct protein was in the patient’s cells, the ‘girders’ were perfect,” Orange says. “It was proof to me that the delivery of this healthy gene truly restored” the cell’s ability to function.

Time will tell just how safe the therapy is in the long run. But in the meantime, the six patients are getting a much longer lease on life than they started out with. Orange saw his patient just last week, at a national conference.

Seeing the boy running around, indistinguishable from children that were not born with a life-threatening mutation, “was definitely one of my finest days in clinical medicine,” he says.

SOURCES: Biffi et al., “Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy”; Aiuti et al., “Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome,” Science published online July 11, 2013.