As reported by Michael Smith, North American Correspondent, MedPage Today, gene therapy, using a lentiviral vector, appears to be safe and effective in two inherited diseases.
Per the scientists, early results from phase I/II trials, conducted by overlapping research teams, suggest the therapy has halted disease progression in three patients with metachromatic leukodystrophy and three with Wiskott-Aldrich syndrome.
Equally important, there is no evidence that the researchers' method preferentially inserts the transferred genes into regions near cancer-causing genes, a shortcoming of earlier approaches, the team reported recently.
"The results obtained from the first six patients are very encouraging," according to Luigi Naldini, MD, PhD (pictured), of the San Raffaele Telethon Institute for Gene Therapy in Milan.
"The therapy is not only safe, but also effective and able to change the clinical history of these severe diseases," Naldini, the senior author on both studies, said in a statement.
Metachromatic leukodystrophy, an inherited lysosomal storage disease caused by a deficiency of the enzyme arylsulfatase A (ARSA), leads to progressive motor and cognitive impairment followed by death, usually a few years after the onset of symptoms.
The enzyme deficiency leads to a build-up of sulfatide in cells of the central and peripheral nervous system, which, in turn, leads to myelin loss and neurodegeneration.
The researchers used the lentiviral vector, which includes some structural proteins (but no genes) from HIV as well as the envelope of the vesicular stomatitis virus, to transfer a functional ARSA gene into hematopoietic stem cells from three patients who had genetic, biochemical, and neurophysiological evidence of the disease, but no symptoms at the time.
Within a month of the re-infusion of the modified cells, the researchers reported, they were stably engrafted at high levels and producing levels of the ARSA protein that were above normal.
Importantly, functional ARSA protein was isolated from the cerebrospinal fluid of all three patients "at levels and activity comparable to those obtained from healthy donor samples," they reported.
One patient has now been followed for 2 years and the others for 18 months, the researchers reported, and all three show normal cognition and language for their ages -- 39, 30, and 25 months.
The oldest patient can stand independently and both walk and run with some assistance, the researchers reported; at the same age, his affected siblings were in wheelchairs and unable to support their heads and trunks.
The other patients have normal motor development so far, but the researchers cautioned that the follow-up time is shorter.
Wiskott-Aldrich syndrome, caused by mutations in the WAS gene, is characterized by infections, microthrombocytopenia, eczema, autoimmunity, and lymphoid malignancies.
In some cases, hematopoietic stem/progenitor cell transplants from matched donors can be curative, the researchers noted, and when there are no such donors, gene therapy is an alternative approach.
But trials with γ-retroviral vectors found an initial clinical benefit, followed by adverse events, such as leukemia or myelodysplasia, that were caused by insertion of the transferred genes near proto-oncogenes, the researchers noted. The cancer-causing genes were then turned on by promoter sequences within the long terminal repeat of the vector.
The lentiviral vector in these studies was designed with a "self-inactivating" long terminal repeat that, they hypothesized, would be safer.
The investigators reported that they used the lentiviral vector, this time encoding a functional WAS gene, into hematopoietic stem cells from three patients with the syndrome, all with recurrent infections, eczema, bleeding, and thrombocytopenia.
With a post-treatment follow-up of between 20 and 32 months, all three children are well and have improvements in platelet counts, immune functions, and clinical score, the investigators reported.
The corrected cells created "a properly functioning immune system and normal platelets," said Alessandro Aiuti, MD, PhD, also of the gene therapy institute.
"The children no longer have to face severe bleeding and infection. They can run, play, and go to school," Aiuti, who was the study's lead author, said in a statement.
In both studies, the investigators said, they were unable to recover any replication-competent lentivirus, and there was no evidence of antibodies to the HIV p24 antigen (an indication of HIV infection).
Their detailed analysis also showed no sign that the lentiviral vector was integrating into cells in ways that might increase the risk of leukemia.
The researchers are continuing to follow the six patients, as well as several others who entered the studies later and for whom results are not yet available.
Illustration: San Raffaele Telethon Institute for Gene Therapy.
MedPage Today (07/11/13)
Abstract (Science; (07/11/13))
Abstract (Science; (07/11/13))