From its earliest conception, gene therapy held the promise of correcting inherited diseases by inserting a normal copy of the relevant gene into somatic cells.
(Donald B. Kohn and Fabio Candotti)
This beautiful concept was working perfectly fine in many animal models. But, after more than a decade of gene therapy clinical trials, we have to admit that it was a very difficult road to any positive outcome. I wrote some doubts about clinical future of retroviral vectors in gene therapy.
But gene therapists aren’t giving up! A recent international study published in New England Journal of Medicine give us new promises for gene therapy of inherited diseases.
What was accomplished in this study that 10 children with severe combined immunodeficiency disease (SCID) were treated by autologous hematopoietic CD34+ cells carrying the gene of interest. In particular they corrected a deficiency of the enzyme adenosine deaminase (ADA). This study was conducted in 2 centers – Hadassah University Hospital (Hadassah, Israel) and San Raffaele Scientific Institute (Milan, Italy).
What amazed me in this story that those 10 kids had no chances to survive due to the absolute fatality of the disease, except one chance – experimental gene therapy treatment. And they are not just surviving, they are having a good quality life!
A child with severe combined immunodeﬁciency disease (SCID), also called “bubble boy” disease, is extremely susceptible to infection because of a malfunctioning immune system. He would not survive outside carefully controlled environments, such as the enclosed area pictured here. © Laurent / Photo Researchers, Inc. (credit: the Dana Foundation )
I’d like to indicate a few things that made this study special:
– all patients are alive after a median follow-up of 4 years;
– cell /gene therapy was autologous due to lack of HLA-matched donors;
– conditioning treatment was nonmyeloablative;
– circulating T-, B- and NK cells contain corrective enzyme (ADA);
– enzyme-replacement therapy (ADA) was completely withdrawn after cell infusion in 8 out of 10 patients;
– excellent and persistent immune reconstitution was achieved;
– after the therapy kids were no longer in need of protective environment to prevent infection.
The accomplishment of this study was gratefully appreciated in the commentary:
Despite the widely publicized adverse events in the X-linked SCID trials, it is vital to dispassionately compare gene-therapy results with those of the current standard of care. Transplantation of parental or unrelated allogeneic hematopoietic stem cells in the approximately 80% of infants with SCID who lack an HLA-matched sibling donor has success rates of 50 to 85%, with a considerable number of patients dying from a host of complications. Certainly, the outcomes of gene therapy for SCID reported in recent trials are at least as good as, and arguably better than, the results reported for allogeneic transplantation, justifying further study of this procedure that, in the case of SCID due to ADA deficiency, has already received orphan-drug status by the European Medicines Agency.
In the commentary, the authors also indicated 6 ways of improving gene therapy protocols to achieve safety and therapeutic efficacy.
Honestly I was not a big believer in success of gene therapies – too much effort and investment for very little outcome. Now, after 20 years of clinical trials it’s become obvious to me that in some cases it will work, in some – not. So, all of approaches should be very selective and there is no universal magic drug. I am just wondering – will stem cell therapy, like gene therapy, face a hard time getting to clinic? Will we learn something from gene therapy trials? Also I think it’s important to believe in things that you do and don’t give up too soon- work something out and troubleshoot.
I’ll finish with an excellent citation from commentary to the paper:
The prospects for continuing advancement of gene therapy to wider applications remain strong. Ongoing and upcoming clinical trials will use safer designs of retroviral vectors, newer types of vectors for viral gene delivery, and emerging methods for direct in situ gene repair. These approaches to the treatment of hemoglobinopathies, hemophilia, muscular dystrophy, congenital retinopathies, neurodegenerative disorders, and other genetic diseases may further fulfill the promise that gene therapy made two decades ago.