First Demonstration of Apparently Fully Curative Gene Therapy

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First Demonstration of " Apparently Fully Curative " Gene Therapy

Zosia Chustecka

Medscape Medical News 2006. © 2006 Medscape

http://www.medscape.com/viewarticle/549132_print

December 11, 2006 (Orlando) — Success with gene therapy in infants

with severe combined immunodeficiency (SCID) reported at the American

Society of Hematology (ASH) 48th Annual Meeting and Exposition spells

" good news for the whole field of gene therapy, " say the researchers.

The results come from a trial of 8 children (aged 7 months to 5.5

years) with SCID caused by a defective gene for adenosine deaminase

(ADA). These infants are so immunocompromised that any infection is

potentially life threatening, and they often spend their short lives

encased in a plastic " bubble. " They were treated with transduced

autologous hematopoietic stem cells transfected with the ADA gene,

inserted via retroviral-mediated transfer.

" All of the children are currently healthy and thriving, " lead

researcher Alessandro Aiuti, MD, from the San Raffaele Telethon

Institute for Gene Therapy, in Milan, Italy, told the meeting. " They

are living normal lives and are going to school and kindergarten. "

They have shown no adverse events related to the gene transfer, and

none have developed severe infections.

All of the infants with longer follow-up who have a completely

reconstituted immune system do not require any treatment, so it

appears that the gene therapy is " curative, " Dr. Aiuti told Medscape.

However, this reconstitution takes time, and before the process is

completed, patients are given immunoglobulins, he added. Before entry

into the trial, 6 of 8 children were on ADA enzyme-replacement therapy.

" This is the first demonstration of an apparently fully curative

gene-therapy transplant, " Emerson, MD, PhD, from the

University of Pennsylvania, in Philadelphia, told Medscape. These

children have gone from " bubble to playground, " he said.

Speaking as the moderator of an ASH press conference at which this

trial was highlighted, Dr. Emerson said the results are good news for

the whole field of gene therapy. " In this trial, the gene therapy

offered tremendous benefits with no toxicity, and it offers real

promise for the future for the potential of gene therapy in more

common and more complex diseases, such as sickle-cell anemia and

thalassemia. "

Also speaking at the press conference, Dr Aiuti explained that

previous attempts at gene therapy for ADA-SCID have not been totally

successful, as the children continued to need enzyme-replacement

therapy (with pegylated ADA). One of the innovations in their own

protocol was the use of the cytoxic agent busulfan, which helps the

engraftment process by " making room for the new stem cells, " he

commented. Busulfan was administered at 2 mg/kg per day on days 3 and

2 prior to the transplant and resulted in a transient myelosuppression

in most patients, although in 2 patients this myelosuppression was

prolonged. " It appears that the greater the extent of neutropenia, the

better the engraftment, " Dr Aiuti commented.

It appears that the gene therapy results in persistent gene

correction, Dr. Aiuti commented. Long-term engraftment of the

transduced cells was demonstrated by stable multilineage marking:

T-cell counts were normal, and there was a restoration of T-cell

function. There were also metabolic benefits — the children did not

need treatment with pegylated ADA enzyme replacement, and 7 of 8

patients showed an increase in both height and weight. " The 1 patient

who didn't was treated at an older age, so there was probably more

damage there, " Dr. Aiuti said.

The median follow-up is 3 years, and the longest is 6 years, but there

is real hope that the effects will " last for a lifetime, " he said.

Dr. Aiuti and colleagues are continuing with this approach and have so

far treated 1 other patient. They concluded that the data so far

" confirm the safety and the efficacy of gene therapy in improving

immune and metabolic function in children diagnosed with ADA-SCID " and

suggested that this approach " may represent a viable solution to

reduce the mortality rates associated with SCID in newborns. "

ASH 48th Annual Meeting and Exposition: Abstract 200. Presented

December 11, 2006.