Navigation Links
Researchers improve gene therapy technique for children with immune disorder
Date:9/11/2012

By including chemotherapy as a conditioning regimen prior to treatment, researchers have developed a refined gene therapy approach that safely and effectively restores the immune system of children with a form of severe combined immunodeficiency (SCID), according to a study published online today in Blood, the Journal of the American Society of Hematology (ASH).

SCID is a group of rare and debilitating genetic disorders that affect the normal development of the immune system in newborns. Infants with SCID are prone to serious, life-threatening infections within the first few months of life and require extensive treatment for survival beyond infancy.

Adenosine deaminase (ADA) deficiency, which accounts for approximately 15 percent of all SCID cases, develops when a gene mutation prohibits the production of ADA, an enzyme that breaks down toxic molecules that can accumulate to harmful levels and kill lymphocytes, the specialized white blood cells that help make up the immune system. In its absence, infants with ADA-deficient SCID lack almost all immune defenses and their condition is almost always fatal within two years if left untreated. Standard treatment for ADA-deficient SCID is a hematopoietic stem cell transplant (HSCT) from a sibling or related donor; however, finding a matched donor can be difficult and transplants can carry significant risks. An alternate treatment method, enzyme replacement therapy (ERT), involves regular injections of the ADA enzyme to maintain the immune system and can help restore immune function; however, the treatments are extremely expensive and painful for the young patients and the effects are often only temporary.

Given the limitations of HSCT and ERT, in the 1990s researchers began investigating the efficacy of gene therapy for ADA-deficient SCID. They discovered that they could "correct" the function of a mutated gene by adding a healthy copy into the cells of the body that help fight infectious diseases. Since then, there have been significant advances in gene therapy for SCID, yet successful gene therapy in patients with ADA-deficient SCID has been seen in only a small series of children due to the difficulty of introducing a healthy ADA gene into bone marrow stem cells and to engraft these cells back into the patients.

"Although the basic steps of gene therapy for patients with SCID have been known for a while, technical and clinical challenges still exist and we wanted to find an optimized gene therapy protocol to restore immunity for young children with ADA-deficient SCID," said Fabio Candotti, MD, one of the study's senior authors, senior investigator in the Genetics and Molecular Biology Branch of the National Human Genome Research Institute at the National Institutes of Health, and chair of the ASH Scientific Committee on Immunology and Host Defense.

To determine whether an enhanced gene therapy approach would improve immunity in children with ADA-deficient SCID, the teams of Dr. Candotti and Donald B. Kohn, MD, director of the Human Gene Medicine Program at the University of California, Los Angeles (UCLA), Professor of Pediatrics and of Microbiology, Immunology, and Molecular Genetics, and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, conducted a clinical trial in 10 patients with the disorder. For the first time, Drs. Candotti and Kohn and their team of investigators compared two different retroviral vectors, MND-ADA and GCsapM-ADA, to transport normal ADA genes into the young patients' bone marrow stem cells as well as two different treatment plans in preparation for receiving gene therapy. Following therapy, investigators found that more bone marrow stem cells were marked with the MND-ADA vector, demonstrating its superiority over the GCsapM-ADA vector.

The investigators also sought to determine whether providing a low dose of chemotherapy prior to gene therapy, known as a pre-transplant conditioning regimen, would successfully deplete the young patients' bone marrow stem cells and make room for gene-corrected stem cells. In four patients, gene therapy was performed without chemotherapy, and the patients remained on ERT throughout the entire procedure to evaluate the efficiency of ERT combined with gene therapy. While these patients did not experience any adverse effects, they also did not experience a significant increase in their levels of the ADA enzyme. They also maintained low absolute lymphocyte counts (ALC) and minimal immune system function, leading the researchers to believe that ERT may weaken the therapy's effect by diluting the number of gene-corrected lymphocytes.

The remaining six patients were treated with the chemotherapy drug busulfan prior to gene therapy and ERT was discontinued prior to the gene therapy procedure. A significant increase in ADA was observed in all six patients; half of them remain off of ERT with partial immune reconstitution findings that support results from prior trials in Italy and the United Kingdom using chemotherapy prior to gene therapy and discontinuting ERT. While the ALC of all six patients declined sharply in the first few months due to combined effects of busulfan administration and ERT withdrawal, their counts increased from six to 24 months, even in the three patients that remained off of ERT. After adjusting the chemotherapy dosage, investigators were able to determine an optimal level for enhancing the efficacy of the gene-therapy-corrected cells with minimal toxicity.

This study is the first to detail comparisons of ADA-deficient SCID patient outcomes between those treated with gene therapy who have not received pre-transplant conditioning while continuing to receive ERT with those receiving pre-transplant conditioning without the administration of ERT. This study is also the first to compare two different viral vectors to transport normal ADA genes into patient bone marrow.

"We were very happy that in this trial we were able to see a benefit in the patients after we modified the protocol," said Dr. Kohn. "Doctors treating ADA-deficient SCID have had too few options for too long, and we hope this will provide them with an efficient and effective treatment for this devastating disease."
'/>"/>

Contact: Claire Gwayi-Chore
cgwayi-chore@hematology.org
202-776-0544
American Society of Hematology
Source:Eurekalert

Related medicine news :

1. Moffitt researchers say race affect likelihood of finding suitable stem cell donor
2. Researchers closer to understanding actions of cells involved in atherosclerosis
3. Case Western Reserve researchers create short-term memories in-vitro
4. Researchers find first evidence for a genetic cause for Barretts esophagus
5. Researchers show cost-effectiveness of HIV testing in drug abuse treatment programs
6. When clinicians and researchers look outside the box
7. Moffitt Cancer Center researchers study childhood melanoma characteristics
8. Pint-size microRNAs show promise against weighty problem, researchers say
9. University of Hawaii cancer researchers discover gene defect responsible for cancer syndrome
10. Moffitt Cancer Center researchers find acidic pH microenvironments in tumors aid tumor cell survival
11. BUSM/VA researchers examine new PTSD diagnosis criteria
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:12/7/2016)... ... ... A quote from Dr. Edward Hallowell, host of CRN International’s “Distraction” podcast ... glimpse into the mind of those people with ADHD. , Dr. Hallowell, a child ... people with ADHD as having “Ferrari engines for a brain, with bicycle brakes.” , ...
(Date:12/7/2016)... ... December 07, 2016 , ... The Cliff ... located in South Lyon, Dewitt, Williamston, East Lansing, Ann Arbor, and Farmington Hills, ... treatment for a brain tumor. , Jason Bauer and his family are longtime ...
(Date:12/7/2016)... ... December 07, 2016 , ... A. Kevin Spann Insurance, a New York-based firm ... Boroughs, is launching a charity drive to raise funds that will benefit the Marine ... of marines and Navy FMF Corpsmen. Working closely with the MCL, the A. Kevin ...
(Date:12/7/2016)... ... December 07, 2016 , ... Delete® - Tattoo Removal and Laser Salon Offers ... Season. Save Up To 33% Off Botox® and Juvederm® Products Now Through December 31, ... with Delightful Deals on Botox® and Juvederm® just in time for the ...
(Date:12/7/2016)... ... December 07, 2016 , ... ... BOC Business Brilliance Awards under the Best New Product Launch category. Gensuite’s entry ... through user experience. , BOC Global Events & Training Group is a professional ...
Breaking Medicine News(10 mins):
(Date:12/7/2016)... -- According to responses from U.S. oncologists that participated in ... with non-small cell lung cancer (NSCLC), treatment decisions are made ... status. The findings of the survey were presented today as ... ) at the 2016 World Conference on Lung Cancer (WCLC) ... survey results revealed an overall high rate of EGFR mutation ...
(Date:12/7/2016)... ALTO, Calif. , Dec. 7, 2016  Varian ... an update to its previously announced plans to separate ... be executed via a tax-free distribution to Varian stockholders ... stand-alone public company that will hold the Imaging Components ... expected to be executed by the end of January ...
(Date:12/7/2016)... , Dec. 7, 2016 Boehringer ... trial in patients with unresectable malignant pleural mesothelioma ... (PFS). The data, presented at the 17 th ... Vienna , showed nintedanib plus ... placebo plus pemetrexed/cisplatin, with a significantly improved PFS ...
Breaking Medicine Technology: