Fanconi Anemia
Seeking better outcomes for children with a devastating disease
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"We're working as hard as we can to take advantage of the investment that's been made here in basic science to change how we take care of patients." David Williams, MD |
It's been just over a year since Krisstina King and David Box received news that turned their family's life upside down.
In June 2003, their daughter Jacy, then 11, was diagnosed with a rare, life-threatening genetic disease — Fanconi anemia (FA). A month later, her older sister, Jo, was diagnosed with the same disease.
Fanconi anemia is caused by a defect in one of several genes that are critical for forming normal blood cells. Children with FA have normal numbers of blood cells at birth, but over time, their bone marrow produces fewer and fewer red cells, white cells and platelets. Some children with FA also have thumb and arm abnormalities, short stature, heart and kidney disease, and other symptoms.
Fanconi anemia is a progressive disease. As their bone marrow fails, children with FA develop life-threatening aplastic anemia. They also have higher than normal risk of developing leukemia. Many patients do not reach adulthood.
Since the girls' diagnosis, life for the Box family has meant coming to terms with devastating news, searching for the best possible medical care and learning how to move forward with hope.
In June 2004, the family moved from Wichita, Kansas, to Cincinnati to be near the Fanconi Anemia Comprehensive Care Center at Cincinnati Children's Hospital Medical Center.
Researchers at work in the Vector Production Facility, one of the new core facilities to support translational research. |
Core Facilities Among the newly created core facilities to assist research on gene therapy trials are: - Cell Manipulations Laboratory
Performs cell manipulations for products needed for gene therapy protocols and other Phase I and Phase II clinical trials. - DNA Sequencing Laboratory
DNA sequencing is the process of analyzing DNA samples to determine the precise order of the chemical building blocks. The DNA Sequencing Laboratory provides rapid, accurate processing of DNA samples. - Translational Research
Trials Office
Assists researchers in designing Phase I trials and obtaining regulatory approval, and provides ongoing support in managing trials. Awards
grants to stimulate innovative research projects. - Vector Production Facility
Provides virus vectors for
use in human gene therapy trials. Vectors are vehicles that can carry and transfer new genetic material into the patient's cells. These virus vectors are produced under strict controls as prescribed by the US Food and Drug Administration (FDA).
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A Disease That's Often Overlooked
Most physicians have little, if any, experience treating Fanconi anemia. It's not unusual, therefore, for the symptoms to go undiagnosed or unrecognized as FA until the child is age 6 or more, when the symptoms of anemia become more pronounced. The children may be tired and pale; they may be susceptible to infections or may bruise or bleed easily. That's what happened with Jacy.
She was born with an extra thumb on one hand, but no one thought to test for FA. A year before she was diagnosed, she started bruising easily. Krisstina was concerned enough to discuss these problems with her doctor, but no alarm bells were sounded. Then, in January 2003, Jacy caught the flu and needed to be hospitalized. Blood tests showed that her platelet count was low. When the counts were still low after four months, Krisstina insisted that Jacy be seen by a blood specialist (hematologist). This specialist began putting pieces together and tested Jacy for Fanconi anemia. Because FA is an inherited disease, when Jacy's test proved positive, Jo was tested and was found to have the disease, too.
Krisstina searched the web to learn where care for FA was best and found the unique program at Cincinnati Children's. After email exchanges with David Williams, MD, director of the Fanconi Anemia Comprehensive Care Center, and Richard Harris, MD, a national leader in blood and marrow transplants (BMT) for FA, she brought Jacy and Jo to Cincinnati for a thorough evaluation in January 2004. The family moved to Cincinnati six months later, attracted by the comprehensive care and the opportunity to be involved in research studies that might offer "the miracle that we need."
Seeking a Better Outcome
Imagine if we could change the outcome for children with Fanconi anemia by correcting the gene defect that causes bone marrow failure.
Researchers in the Division of Experimental Hematology at Cincinnati Children's have spent years preparing for a highly experimental gene transfer trial in which they will attempt to treat FA by replacing the defective gene. This will be a Phase I trial, the earliest stage of research using a human subject, testing the treatment's safety. The team plans to enroll 15 patients over the next three years and to monitor them for up to 15 years.
Jo and Jacy Box were among the first to agree to be part of the gene transfer trial and are very excited about being involved in this pioneering research. "We think it's kind of awesome," their mother says. They know that the gene transfer may not cure their disease, but hope that it might make a difference or help other children in the future. "It might help them live a more normal life," Krisstina says, adding, "We decided long ago that we're more than willing to do what we can to help others and ourselves."
Building the Resources to Transform Care
A project like this moves forward with a combination of determination, great hope and even greater caution. Cincinnati Children's is determined to change outcomes for children by moving new knowledge from the laboratory into the clinic to help patients — and we're backing that vision of improved care with the type of investment needed to make it happen.
The medical center has made dramatic investments to put all the pieces in place.
We've added more than 300,000 square feet of research space since 1991. In the spring of 2004, we broke ground for a 12-story, 415,000-square-foot building that will further increase research capacity. We've recruited world-class physicians and scientists to join the already strong clinical and research teams in Cincinnati. We've created an infrastructure that gives investigators resources that maximize their ability to work creatively and effectively, and we've established "core" facilities to support investigators by enhancing their access to cutting-edge technology and data analysis.
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At left: Krisstina King with her daughters
"We decided long ago that we're more than willing to do what we can to help others and ourselves."
Krisstina King |
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Assembling the Team for Translational Research
The climate for research at Cincinnati Children's has created a sense of excitement and possibility that is attracting scientists who want to push the boundaries of knowledge.
The gene transfer trial for Fanconi anemia is led by a team of physicians and scientists who have joined Cincinnati Children's within the last three years to work in an environment that encourages and supports translational research.
The team is led by David Williams, MD, a world-renowned physician and scientist who established and directs the Division of Experimental Hematology and the Fanconi Anemia Comprehensive Care Center.
He comments: "I wanted to go to an institution that was serious about translational research and where pediatrics and children weren't an afterthought. There are very few institutions in the country that are research-intensive pediatric hospitals. The scientific environment here is extraordinary."
Another team member is Christof von Kalle, MD, PhD, who is internationally honored for groundbreaking research on gene therapy trials. Dr. von Kalle came from Germany to lead the Molecular and Gene Therapy Program in the Division of Experimental Hematology. "I think this is the premier location to do this type of research," he says. "To be successful in translational research, you need a structure that allows you not only to do cutting-edge molecular work in the laboratory, but to try to push it all the way through the system to the bedside. That is happening in this institution. It's just very impressive, and quite unique."
The clinical director of the Fanconi anemia gene transfer trial is pediatric hematologist Patrick Kelly, MD. "I love this hospital," he says. "I've been around the country, and the collective expertise for pediatrics here is unparalleled. You have access to everything for your patients. The laboratory bench is literally around the corner."
Attracted by the unique environment, this talented team is "working as hard as we can to take advantage of the investment that's been made here in basic science to change how we take care of patients," says Dr. Williams.
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Richard Harris, MD, a national leader in blood and marrow transplants for Fanconi anemia. |
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Patrick Kelly, MD, clinical director of the Fanconi anemia gene transfer trial. |
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Christof von Kalle, MD, PhD, leads the Molecular and Gene Therapy Program in the Division of Experimental Hematology. |
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David Williams, MD, director of the Division of Experimental Hematology and the Fanconi Anemia Comprehensive Care Center. |
Hope: Can We Cure the Genetic Defect?
The FA gene transfer trial will try to insert genetic information missing in the blood-forming stem cells. The research team has embedded a normal FA gene in a retrovirus vector. The vector, Dr. von Kalle explains, will act like a gene taxi. It will transport the gene into the patient's own blood stem cells. Retroviruses are used as agents because these viruses have a unique ability to incorporate themselves into the recipient cell's DNA. The virus is modified so it can't cause infection but retains its ability to implant itself.
Once the gene is inserted, each time the cell divides, the new cells will include the normal gene. The researchers hope that this gene will multiply enough to provide normal production of blood cells, preventing aplastic anemia and leukemia.
Safety Is the First Priority
If gene replacement works, it could revolutionize the care of children with Fanconi anemia. But the trial is not without its dangers. Gene therapy is a new field, and there is much yet to be learned.
Two years ago in France, a gene therapy trial for a different disease was temporarily halted when two of the children in the study developed leukemia. In that study, gene therapy restored the immune system of nine children with severe combined immunodeficiency disease, a uniformly fatal disease. This success was somewhat overshadowed by concern about the treatment causing leukemia, another life-threatening disease. In the United States, the National Institutes of Health temporarily halted all trials using retroviruses to insert genes into blood stem cells.
In a piece of breathtaking research on the leukemic cells from the children in France, Dr. von Kalle and his research team discovered that the vector carrying the therapeutic gene had inserted itself next to and activated a gene that plays a role in causing childhood leukemia. Analytic techniques Dr. von Kalle developed allowed him to do this research with astonishing speed — in just two weeks.
His work "rapidly converted a mysterious and very frightening event into a clear and focused pathway toward preventing such complications in the future," according to the American Society for Gene Therapy, which honored him with the 2003 Young Investigator Award.
With the insights Dr. von Kalle provided, gene therapy trials have resumed in the United States and elsewhere, on the understanding that researchers must monitor vector insertion sites. Investigators around the world rely on his highly sensitive methodology for this safety analysis.
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Translational Research Translational research may be defined as the effort to transfer discovery research from the laboratory into human trials and to transfer observations from the clinic back into questions that are attacked by basic scientists. |
The Trial Begins
At Cincinnati Children's, work is moving forward with cautious optimism. "We're very proud of the experimental therapy we've developed and the care we've taken to minimize risk," says Dr. Kelly. "These are patients who need this. But we have to be very careful about promising anything. We're still very early in the process of learning how to correct genes and stem cells."
The immediate goal is to determine the safety and side effects of inserting the normal gene into blood-producing cells. Stem cells will be collected from the patient's bone marrow. The gene insertion will take place in the laboratory, where the cells will be tested for safety issues and stimulated to allow the gene insertion to occur. Only then will they be re-infused back into the patient.
As a safety precaution, patients will receive a very small number of manipulated cells in this first trial. These few cells will have to compete with the much larger number of defective cells still in the child's bone marrow and may not be able to make enough corrected blood cells to cure the defect. But if this first trial proves to be safe, the intensity of treatment will be "ratcheted up" says Dr. Kelly.
While this work proceeds, researchers in the Division of Experimental Hematology are preparing to apply gene transfer techniques to other devastating conditions, beginning with brain tumors.
