HIV kills nearly two million people every year, but scientists in Italy say they've found a way to use the virus to actually save lives. In a pair of studies published today in the journal Science, a team of researchers from the San Raffaele Telethon Institute for Gene Therapy (TIGET) describe a method by which HIV was used to treat two rare, but deadly genetic diseases in children — leukodystrophy, which cripples the nervous system, and Wiskott-Aldrich syndrome, which ravages a child's immune system.
The technique, developed over the course of 15 years, involves replacing defective genes with healthy copies delivered with viral vectors derived from HIV. The Milan-based team, led by Dr. Luigi Naldini, conducted years of laboratory tests before testing the method on a group of 16 patients in 2010 — six with Wiskott-Aldrich syndrome and 10 with metachromatic leukodystrophy. Three years later, six of these children (three from each group) are now showing encouraging signs of recovery, with Naldini describing the development as a breakthrough in gene therapy treatment.
"Today, they are normal children."
It's too early to say whether Naldini's treatment offers a complete cure for either disease, though he says early signs are encouraging.
"We can't speak in definite terms, of course, because it's only been three years," Naldini said in a telephone interview with The Verge. "But the three children with metachromatic leukodystrophy were expected to become very ill by this point, based on the disease progression. Today, they are essentially normal children, and the disease has not developed or progressed."
The three children suffering from Wiskott-Aldrich have seen similarly positive improvements to their immune systems, and have stopped experiencing any of the spontaneous bleeding that the syndrome can cause. Naldini says the other 10 children involved in the study are showing many of "the same patterns" as the six cited in his team's studies, though it's too early to formally evaluate their progress.
Neither Wiskott-Aldrich syndrome nor metachromatic leukodystrophy are very common. Wiskott-Aldrich cases range between one and ten per million males worldwide, and is even rarer in females. Metachromatic leukodystrophy is only slightly more common, affecting one in an estimated 40,000 to 160,000 individuals on a global basis, according to the National Institutes of Health.
Rare, but deadly
Both are caused by a deficiency in a protein critical to early development, and for those affected, the results can be tragic. Children who develop metachromatic leukodystrophy early in life — within their first year — typically die before they reach the age of five, their cognitive and motor skills quickly deteriorating. Wiskott-Aldrich syndrome targets platelet blood cells that are critical to clotting, resulting in profuse bleeding. It severely weakens the immune system, making a child more susceptible to autoimmune diseases and cancer.
There is so far no cure for metachromatic leukodystrophy, and the only way to cure Wiskott-Aldrich is through a bone marrow transplant. But these transplants carry tremendous risk, and it can be difficult to find suitable donors.
"Unless the donor is your identical twin, there's always a risk that you may reject the transplant, or the transplant may reject you," Naldini says. "In that case, it becomes deadly."
Naldini's method, by contrast, relies on a patient's own stem cells rather than donors. Hematopoietic stem cells are withdrawn from a child's bone marrow, and defective genes are replaced with corrected ones. This approach is generally known as gene therapy — a process whereby therapeutic proteins are packaged in "vectors" used to inject DNA into the body. Researchers have spent years exploring the treatment, but its long-term effects remain unknown. The advantage to using stem cells, Naldini notes, is that patients don't have to find a suitable donor, and the transplanted proteins should "self-maintain" over time.
Researchers see potential for other applications
Naldini says only a small percentage of the HIV virus was used to create the vector, adding that stringent tests and molecular analyses were conducted to promote safety. Naldini began experimenting with HIV in 1996, as part of an investigation into the infectious capacity of the virus. He eventually realized that HIV offered an efficient way to transfer genes, and began deriving vectors from it.
"The biggest issue is not so much the risk of [transmitting the] virus," he explains. "It's more a risk of integrating the vector into the genome."
Naldini acknowledges that his team will need to closely observe their patients over the coming years to ensure that the treatment proceeds smoothly, but the results published today give him hope that similar approaches could be used to treat other genetic disorders.
"In many ways these two diseases are paradigmatic of their [respective] disease families," he says. "So I think this could be applied to other cases, and we have already begun looking into it."