Gene Therapy for FA
New Clinical Study Open to FA Patients
In late 2011, Seattle Children’s and Seattle Cancer Care Alliance opened enrollment in the first-ever clinical trial of Lentiviral Vector Gene Therapy for patients with FA. The researchers hope this new method of gene correction will be a safe and effective alternative to bone marrow transplantation. Many FA patients lack a good donor match or are too ill for transplant. The study is limited to patients in FA complementation group A and without an HLA-matched sibling donor. The main purpose of this ground-breaking study is to measure safety. That’s why only adults (>18 years of age) are being enrolled initially. Expansion to include children may occur later.
Families, patients, or physicians should contact the FA Center for study details and updates.
- For more information about eligibility for the study: NCT01331018
- For a more in-depth description of the gene therapy trial, see Pediatric BMT Update (Spring 2012)
A New Way to Correct the Faulty FA Gene
Even as the gene therapy trial gets underway, FA researchers at the Hutchinson Center, Seattle Children’s, and the UW are already looking ahead to the next generation of therapies for FA and other rare inherited diseases. One promising line of research involves the use of “homing endonucleases” and other DNA-targeted agents to pinpoint and repair FA gene defects within the patient’s own cells. To pursue this type of precision-targeted gene correction, Andrew Scharenberg, MD, of Seattle Children’s recently received a multi-million dollar grant from the NIH to support a 7-laboratory team in the Northwest Genome Engineering Consortium.
New Directions in FA Research
Dr. Akiko Shimamura from SCCA made comments inte Fanconi Anemia Research Fund, Inc Newsletter http://www.fanconi.org/images/uploads/other/FN50.pdf:
- Scientists are now screening for drugs that might correct the FA pathway in cells. When the FA pathway is working correctly, DNA damage causes a small molecule called ubiquitin to attach to the FANCD2 protein (a process called ubiquitization), enabling DNA damage repair. Researchers can now test for the add-on of the ubiquitin molecule and are screening for compounds that might effectively result in the addition of ubiquitin and therefore correct the FA pathway.
- Scientists can take adult skin cells, introduce four different genes and re-program these cells to become induced pluripotent stem (iPS) cells. IPS cells can replicate themselves and can be cultured to become any tissue in the body. Gene correction combined with iPS cell technology has corrected sickle cell anemia in mice. Scientists hope that this method could eventually cure the FA deficiency in bone marrow cells.
- Genomics technology allows scientists to sequence the entire genome at a fraction of earlier costs. This methodology could be used to identify quickly and accurately all disease-causing mutations.
Scientists at the Fred Hutchinson Cancer Research Center have developed a clinically successful method of increasing the number of
blood-forming cells available from a single cord blood unit by expanding the cells in the laboratory. Patients undergoing a cord blood transplant who received these expanded cells recovered their neutrophil counts in half the time compared to those who received cells that had not been expanded. This technology could significantly improve the outcomes for patients undergoing cord blood transplantation, which is particularly important for patients who lack a suitably matched donor.
New Sources of Healthy Stem Cells
Umbilical Cord Blood
Several researchers at SCCA are attempting to boost the number of active stem cells available in umbilical cord blood, a method that could eventually improve options for FA patients without matched donors. For more technical details on cord blood transplants, see the following articles:
Other SCCA researchers are working on deriving blood stem cells from reprogrammed skin cells or so called induced pluripotent stem cells. This approach would allow the generation of large numbers of blood stem cells from skin fibroblasts or other cells. Again, this might give FA patients without matched donors another option for replacing their faulty blood cells.
For more technical details on use of pluripotent stem cells, see the following articles:
New Insights on How FA Disrupts the Cell
Another major SCCA research effort with implications for future FA treatments is led by Toshi Taniguchi, MD, PhD, who made landmark discoveries about DNA repair mechanisms while researching Fanconi anemia at Dana-Farber Cancer Research Institute in Boston. Now at the Hutchinson Center, Taniguchi remains focused on investigations into FA, DNA repair, and cancer susceptibility.