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    Sandra d'Azzo: All the Right questions

    AnswerEnzyme-replacement therapy.

    Question: What is Lauren Ryan’s best hope for a cure?

    If you’re a JEOPARDY! fan like 13-year-old Lauren Ryan is, you know that sometimes the question is really the answer. One investigator at St. Jude Children’s Research Hospital has dedicated her career to posing the crucial research questions that offer hope to children like Lauren.

    Alessandra d’Azzo, PhD, studies three rare genetic diseases with names that would challenge even the most astute game show contestant: GM1-gangliosidosis, sialidosis and galactosialidosis. These diseases are part of a group of diseases called lysosomal storage disorders.

    Lysosomes are the cell’s recycling centers. These tiny bags of enzymes break down biological materials into their basic building blocks; the recycled materials are either used to make new molecules or are discarded. If an enzyme in a lysosome is defective or missing, the lysosome can’t do its job, and the product that should be broken down accumulates. Because the cells no longer function properly, the body’s organs don’t work correctly, bones don’t form normally and muscles don’t develop as they should. Most children with these disorders also experience brain damage that leads to cognitive and motor delays.

    “If you lack even one of these enzymes, you have a devastating disease,” says d’Azzo, who holds the St. Jude chair in Genetics and Gene Therapy, a position endowed by Jewelers for Children.

    What is teamwork?

    During the past couple of decades, d’Azzo has emerged as one of the world’s top researchers in the field of lysosomal storage disorders. She is one of the reasons Kristin Weader and Vincent Ryan decided to bring their daughter to St. Jude for treatment. At St. Jude, Lauren is followed by John Cunningham, MD, of Hematology. But the teenager has also grown to know and love the researcher who toils in the lab to find a cure. It’s the kind of teamwork that makes St. Jude unique.

    Every summer, Lauren and her parents travel from Pennsylvania to Tennessee for her annual checkup. “Dr. d’Azzo usually comes in with Dr. Cunningham after all the tests are done,” Kristin explains. “He goes over the test results with us, and she updates us about her research and the progress that she’s made during the year.”

    Lauren has galactosialidosis (pronounced gal-ACT-o-sy-al-i-DO-sis), a disease so rare that her parents have never even met another child with the same condition. When Lauren was born, doctors in Pennsylvania told her parents that she would not live to be 1 year old, and if she did live past that age, she would have severe mental retardation. Lauren has respiratory and digestive problems, as well as issues with her heart, eyesight, hearing and joints. But she is a bright and compassionate young lady who plays the piano, sings in her school’s chorus, enjoys Harry Potter books and dreams of auditioning for the JEOPARDY! game show. Currently, her disease is progressive and incurable, with Lauren’s physicians limited to managing her symptoms. But d’Azzo is working feverishly on research that offers hope to Lauren and her parents

    What is progress?

    While pursuing doctoral degrees in Italy and the Netherlands, d’Azzo never dreamed that so much of her career would be dedicated to finding cures for three related diseases. “I chose the three out of totally serendipitous findings,” she says. “I’ve found that in science the best possible discoveries are those kinds—it’s not what you actually plan or expect to find, but the unexpected finding that is important.”

    She began by studying an enzyme called beta-galactosidase. d’Azzo discovered that children with the disease GM1-gangliosidosis inherit a defect in that enzyme. Other children have a deficiency in an enzyme called sialidase; those patients have a disease called sialidosis.

    “Out of a sheer coincidence, I discovered the primary defect in a third group of patients,” d’Azzo says.

    She discovered that in one group of patients, a beta-galactosidase deficiency was accompanied by another, even more important defect: a problem with the sialidase or neuraminidase enzyme that was defective because of the loss of an additional enzyme, protective protein/cathepsin A, or PPCA. Those patients—including Lauren Ryan—have galactosialidosis.

    “I developed my whole program around these three enzymes,” d’Azzo says. “It has been incredibly rewarding because we have learned a great deal about the diseases themselves.”

    She also developed laboratory models for all three diseases. Then her task was to find a way to replace the missing enzyme. In theory, if the enzyme is introduced into a patient’s bone marrow, then the bone marrow would begin producing normal amounts of that enzyme.

    “We are now getting to the point that we can translate what we have found back into the clinic,” d’Azzo says. “If you have a way to provide these children with a continuous source of the missing enzyme, you could cure a lot of the characteristics of the disease.” But the enzymes are big molecules, much too large to cross the protective barrier that shields the brain from harmful substances in the blood stream. Since the diseases d’Azzo studies affect the central nervous system, overcoming this blood-brain barrier is important.

    d’Azzo looked for a way to produce sufficient quantities of the enzyme so that it could be administered as a drug to affected children. Eventually, she and her colleagues turned to an unlikely source: the butterfly. That’s right, cells from these insects can be infected with a baculovirus that contains a desired gene. The infected insect cells then produce the necessary enzyme. d’Azzo then figured out how to crystallize large amounts of that enzyme. “It turned out to be perfect,” she says. Laboratory mice with galactosialidosis responded well to the enzyme. “Their systemic organs were all corrected,” d’Azzo says.

    In the next couple of years, d’Azzo hopes to work even more closely with St. Jude clinicians to move toward providing enzyme replacement therapy to children like Lauren. It is a long and involved process that demands teamwork, time, patience and resources. Eventually, the enzyme might be produced in the hospital’s Good Manufacturing Practices facility, a production center for drugs, vaccines, proteins, gene-based molecules and other biological products.

    d’Azzo says St. Jude is the perfect place to pursue that dream. “It’s very rare to find an array of absolutely fantastic scientists, clinicians and core facilities in one place,” she says. “I think we can absolutely make a difference. We have made gigantic steps, but we still have a lot to learn. I am sure that eventually this knowledge we are gaining will be translated into helping children.”

    What is hope?

    Meanwhile, Lauren is not waiting around for that elusive cure; she’s far too busy planning her future. Lauren is excited about the possibility of playing soccer in a new league that accommodates kids with special needs. She plans to make the honor roll in the seventh grade, as she missed it by only .13 of a point last year. And she’s debating what to be when she grows up…Should she be a nurse? A school teacher? A librarian? “I’m still trying to think of what I want to do,” she admits.

    Kristin says her daughter is already a teacher—a person who provides daily lessons about how life should be lived. “Lauren is someone who willingly gives up her whole allowance (and then some) to put in the offering at Bible school because “the hungry people in the world need it more than me,’” Kristin says. “She’s someone who has taught me more about love and courage than anyone else....Someone who has a strong faith and believes with all her heart that God has a plan for her life. And so do I!” 

    When discussing d’Azzo’s research, Kristin’s voice breaks with emotion. “Dr. d’Azzo is really dedicated to finding a way to help Lauren,” she says. “I feel so blessed. It’s truly a miracle that God has put somebody on this earth who is specifically working on my daughter’s disease.”

    Reprinted from Promise magazine, autumn 2005

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