All Posts Conferences Newborn Screening and Genetics

Newborn screening ‘ecosystem’ continues to improve

Maurizio Scarpa, MD, PhD, director of the Regional Coordinating Center for Rare Diseases of the European Reference Network for Hereditary Metabolic Diseases at Udine University Hospital in Udine, Italy, stands at the podium.

By Melanie Padgett Powers, writer

Newborn screening is known primarily as the heel stick a newborn gets to test their blood for certain genetic diseases. But that simple description understates the profound effect newborn screening has had on families, as public health celebrates 60 years since the beginning of routine newborn screening in the US.

“Newborn screening is one of the major achievements in the history of medicine, in public health,” said Maurizio Scarpa, MD, PhD, director of the Regional Coordinating Center for Rare Diseases of the European Reference Network for Hereditary Metabolic Diseases at Udine University Hospital in Udine, Italy. “The diagnosis of an asymptomatic child allows the choice of the best care and the best treatment. Newborn screening is indeed the way to go for a treatable disorder in order to limit the progression of the disease or the effect of the disease.”

Scarpa was one of four speakers at the 2023 APHL/ISNS Newborn Screening Symposium keynote session, “60 Years of Screening: A Time to Celebrate and a Time to Reflect,” in Sacramento, California in October. The keynote speakers examined newborn screening in a SWOT analysis framework—looking at the program’s strengths, weaknesses, opportunities and threats.

Newborn screening was created in 1963, after Robert Guthrie, MD, PhD, developed a blood test to screen for phenylketonuria (PKU) in New York. When discovered early, PKU can be treated with a lifelong specific diet and special nutritional supplement. Without treatment, children can develop permanent intellectual disabilities.

In the past 60 years, more than 750 million babies have been screened for PKU, Scarpa said, with 60,000 cases identified and treated. “An entire football arena can be filled up with all the children saved by [PKU] newborn screening,” he said.

Now PKU is one of more than 30 conditions recommended for US states to screen as part of their routine newborn screening programs. Most laboratory testing that supports state newborn screening programs is conducted by a public health laboratory.

Technological advancements in newborn screening

Newborn screening is so much more than that heel stick, said Jerry Vockley, MD, PhD, of the University of Pittsburgh Schools of Medicine and Public Health. Vockley maintained that the program is more of an “ecosystem.”

“It’s not just the test. It’s not just the follow-up. It’s not just the treatment,” Vockley said. “It’s actually a whole system of pieces that need to be in place for this to be successful.” This includes collaborations with multiple stakeholders, including patients, parents and regulatory agencies.

But as technology advances, the testing process is becoming more convoluted. Now, the addition of next-generation sequencing—which includes whole exome sequencing and whole genome sequencing—allows laboratories to examine the genetic information in a person’s DNA in a much shorter time. This is not a routine part of newborn screening, as laboratory professionals are still learning how to interpret and analyze results with this newer technology.

DNA sequencing can be helpful as a secondary test—after the initial newborn screening heel prick—to determine whether a screening was truly positive for a disease or whether it was a false positive, said Robert L. Nussbaum, MD, chief medical officer at Invitae, a genetic testing company.

In a true positive test, when biomarkers are ambiguous, DNA sequencing can help narrow down the diagnosis and determine what condition the newborn has, Nussbaum said. He cited a study that showed that DNA sequencing was helpful in determining whether there was an unknown genetic explanation for newborns struggling in neonatal intensive care units.

Another new technology that could benefit newborn screening is artificial intelligence, Scarpa said. “I think newborn screening should … start thinking about how to use artificial intelligence so newborn screening can be efficient, valid and with equity and equality for all the newborns that are tested.”

He pointed to one study with data from thousands of newborns in which computer algorithms were able to decrease the false positive rate of metabolic disorders by 25%. “We can indeed create algorithms that can help us in making our newborn screening even more precise, sensible and with an even bigger sensitivity to what we have now.”

However, he added, “We need to do this in a very passionate way, but in a very organized way. … But I think that this is a way that we cannot ignore, and we need to be prepared in order to add this kind of technology.”

Gene editing to cure sickle cell disease

Another advancement connected to newborn screening is gene editing to cure disease. Sickle cell disease (SCD) is one of the conditions included in newborn screening in all US states and territories. SCD is the most common inherited clinically significant blood disease in the country. It affects one in 400 African American newborns in the US.

The SCD survival rate to adulthood has improved significantly, thanks largely to the newborn screening process that detects SCD in the first week of a baby’s life. However, SCD can be incredibly painful and damage multiple organs.

Haydar Frangoul, MD, MS, shared how his team has successfully used CRISPR/Cas9 gene-editing technology to cure patients with SCD. He is the medical director of pediatric hematology/oncology at Sarah Cannon Pediatric Transplant and Cellular Therapy Program at TriStar Centennial in Nashville, Tennessee.

“Gene editing tools allow scientists to make very precise changes in the DNA,” Frangoul explained. “These tools allow genetic material to be disrupted, deleted, corrected or inserted at a precise location.”

Frangoul’s team is using gene editing to increase fetal hemoglobin. Before birth, a fetus’ hemoglobin is 95% fetal hemoglobin, he explained. These babies are born seemingly without SCD; their SCD symptoms arise only after their fetal hemoglobin is replaced by hemoglobin A a few months after birth. Previous studies have shown that those with SCD who also had higher rates of fetal hemoglobin as they aged—known as hereditary persistence of fetal hemoglobin—had less severe SCD symptoms.

Therefore, in the CLIMB SCD-121 trial, Frangoul and his team “basically turn patients with sickle cell disease into patients with hereditary persistence of fetal hemoglobin,” he said. To do the gene editing, the researchers collect a patient’s stem cells and “shock the cells” allowing CRISPR/Cas9 to enter. “I think the little kids really get a kick out of it when I say I’m going to electrocute their cells to fix them,” Frangoul said.

CRISPR/Cas9 breaks the DNA at the location needed. The patients undergo chemotherapy to destroy their bone marrow before the gene-edited cells are infused into them.

In the CLIMB SCD-121 trial, Frangoul’s team is using gene editing to decrease the BC11A gene. That suppression increases the production of gamma globin antibodies and increases fetal hemoglobin. The multicenter international trial started over four years ago. So far, 35 patients, ages 12 to 35, have undergone the gene editing. Before the treatment, the median number of vaso-occlusive crises—when SCD pain and other symptoms worsen—ranged from four to five per year. After the treatment, up to three years later, 94% of the patients had not had a SCD crisis or complication, and none of the patients were admitted to a hospital.

The ongoing impact of newborn screening

Gene editing to cure diseases, DNA sequencing to discover the cause of mystery illnesses, and artificial intelligence to improve screening results: all of these extraordinary promises of medical diagnosis and treatment would not have been possible without the creation of newborn screening 60 years ago.

Melanie Padgett Powers is a freelance writer and editor specializing in health care and public health.

The Newborn Screening Symposium, co-sponsored by APHL and the International Society for Neonatal Screening, was held in Sacramento, California, and online October 15-19, 2023.

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