NCATS-Supported Consortium Charts New Course for Rare Immune Diseases

Translational Science Highlight

  • NCATS-supported research consortium scientists are conducting natural history studies and defining rare genetic diseases. By studying related rare diseases, the research team breaks down translational barriers in sharing knowledge and developing therapies for rare immune system disorders.

While in medical school in the early 1970s, Jennifer Puck, M.D., served a medical rotation at the Navajo Nation in Arizona and New Mexico. After her rotation, she subsequently learned that the Navajo had an unusually high incidence of severe combined immunodeficiency (SCID), an inherited disorder that robs the immune system of its ability to fight infections. Decades later, Puck, through the NCATS-supported Primary Immune Deficiency Treatment Consortium (PIDTC), again would work with the Navajo to help change the outlook of the disease.

Today, Puck is a pediatric immunology specialist at the University of California, San Francisco (UCSF), where she studies SCID and other rare immune system diseases. At UCSF, she joined the PIDTC, a research collaborative of 45 institutions in the United States and Canada headed by pediatric immunologist Morton Cowan, M.D., and part of NCATS’ Rare Diseases Clinical Research Network (RDCRN). The PIDTC’s work is ushering in a new era of understanding about disorders that can devastate the body’s ability to fend off disease.

Cowan, professor emeritus of pediatrics and former chief of the Pediatric Allergy, Immunology and Bone Marrow Transplant Division at UCSF, also has a long-time connection to the Navajo; he has worked with a group in Arizona for more than 25 years and first reported the gene mutation that causes SCID in Athabascan-speaking Native Americans (Navajo and Apache Indians). Cowan is principal investigator of the PIDTC, which focuses on better understanding and developing therapies for three types of rare primary immune deficiencies: SCID, Wiskott-Aldrich syndrome and chronic granulomatous disease. The PIDTC is supported by the RDCRN and NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The RDCRN program supports rare diseases research through clinical studies and facilitating collaboration, study enrollment and data sharing. Scientists from different disciplines at hundreds of clinical sites around the world work together with patient advocacy groups to study more than 280 rare diseases.

“RDCRN support has helped overcome critical translational science barriers in better understanding several rare immune disorders,” said Tiina Urv, Ph.D., program director for the RDCRN in the NCATS Office of Rare Diseases Research. “PIDTC researchers are working together on large studies to reveal insights into disease biology, the long-term effects of treatments and the potential for improved therapies.”

SCID includes several rare disorders caused by mutations in genes involved in the development and function of immune cells that fight infection. Babies with SCID often die before age two unless they receive gene therapy, enzyme replacement treatment or a hematopoietic stem cell transplant. For nearly 50 years, clinicians have been using transplants — which are designed to help re-establish the recipient’s blood cell-forming abilities and restore the immune system — to treat children with SCID. Based on PIDTC studies, about 60 percent to 70 percent of children who receive stem cell transplants for SCID live at least into their 20s or 30s.

Early Screening and Treatment

Despite general improvements in patient survival, clinicians treating patients with immune deficiency disorders often used approaches to therapy based on small numbers of patients seen at individual institutions. To make progress, these providers needed a centralized organization to help coordinate research studies, establish collaborations and develop treatment standards.

Morton Cowan, M.D.,

Dr. Mort Cowan sees patient Everett Schmitt, 18 months, and his mother Anne Klein at the University of California, San Francisco (UCSF). Everett was treated at UCSF for severe combined immunodeficiency (SCID) through a bone marrow transplant at seven weeks old, where doctors there developed a newborn screening test for SCID.

PIDTC was launched in 2009 to tackle these challenges, and consortium scientists quickly found a translational roadblock in their way: the lack of natural history studies of immune deficiency disorders. These studies help investigators understand how diseases progress over time, how patients have been treated and the effects of those treatments. This information would enable researchers to compare and evaluate therapies and provide a shared foundation for the development of treatment standards.

Puck and her colleagues also had another concern: it was difficult to know which babies had SCID until they got sick. Puck had developed a newborn screening test a few years earlier, and she and Cowan subsequently led a PIDTC-funded pilot project and clinical trial to study the effectiveness of large-scale screening of newborns for SCID in the Navajo Nation, where Cowan already held annual SCID clinics. The screening test proved successful and was instrumental in convincing the Navajo Nation to institute screening throughout the reservation.

A subsequent study of 11 states using newborn screening for SCID showed the disorder was much more common than previously thought. Rather than an incidence of one case in 100,000 newborns, scientists reported that the figure was closer to one in 58,000.

The importance of screening and early detection was quickly evident. In a 2014 New England Journal of Medicine study, Cowan; Puck; NIAID’s Linda Griffith, M.D., Ph.D.; and their PIDTC colleagues demonstrated that newborns who were diagnosed with SCID between 2000 and 2009 and treated with a stem cell transplant within three and a half months of birth tended to fare much better than those receiving a transplant later in life, primarily due to an improved ability to fight infections. Newborn screening for SCID is used in all but two states in the U.S.

“We demonstrated how effective transplants for SCID had become and how important it is for patients to be diagnosed and transplanted early,” Puck said. “It really changed people’s view of the disease and what was possible.”

Studying long-term health

As more children with SCID are living longer with treatment, PIDTC researchers have taken the lead in examining the long-term effects resulting from transplants, such as neurocognitive difficulties, lung disease, and fertility and hearing problems.

PIDTC-supported researchers currently are completing a large, retrospective study of the long-term health of nearly 600 SCID patients who have received a stem cell transplant since 1982. Such studies have also revealed more about SCID biology and disease types.

The specific genetic form of SCID matters; it affects the disease’s progression and the therapy used. “Previously, we could only look at symptoms and disease effects, which were often based on the levels of certain types of immune system cells, including infection-fighting B and T cells,” Cowan said. “Now we are beginning to put patients in categories based on SCID genetic make-up and how they respond to therapy.”

PIDTC investigators currently are recruiting patients for forward-looking prospective trials as well.

“We want to find out what patients’ immunity and overall health and lifestyles are like years after treatment,” Cowan said. “We have about 140 surviving patients with SCID after 20 years. Along with European collaborators, we’ll have the largest report of survivors who are living 20 years after their transplant.” In addition, to date, they have enrolled nearly 250 newly diagnosed patients with SCID to study how their immune systems fare after treatment and over time.

Other PIDTC-led studies focus on improving the treatment of SCID using gene therapy, in which a specially modified virus delivers a correct copy of a faulty gene to the patient. SCID was the first disease treated with gene therapy, and some patients unexpectedly developed cancer following treatment. PIDTC investigators are also examining the use of the chemotherapy drug busulfan, often used in preparing a patient’s immune system for a stem cell transplant. Researchers are conducting a multicenter prospective trial of newly diagnosed babies to identify the safest, lowest effective dose of the drug.

Puck credits the PIDTC with making such research studies possible.

“These are rare disorders, and no single institution has enough patients to move the field forward,” she said.

“SCID isn’t one disease,” she added. “It involves more than a dozen different genes that we know of and many others we don’t. We’re learning what treatments work best for different types of disease and patients. We continue to ask questions that can change practice and the care of patients, and the consortium is playing an important role in making it happen.”

Posted January 2018