Screening and Drug Development Working in Tandem
Sequencing technologies have advanced and become more sophisticated as well as less costly, so interest in expanding newborn screening through newborn genome sequencing has increased. In fact, many states currently have incorporated genetic testing into newborn screening for conditions without biochemical markers. Additionally, newborn genomic sequencing is also used for further testing in infants with abnormal biochemical screening results.6
Genomic sequencing “identifies nucleotide changes that are the underlying etiology of monogenic disorders.”6 Its use could potentially enable identification of over 500 genetic disorders for which an newborn screening assay is not currently available, said Dr. Hu.
“Molecular DNA analysis has been integrated into newborn testing either as a first- or second-tier test for several conditions, including cystic fibrosis, severe combined immunodeficiency, and spinal muscular atrophy (SMA),” Dr. Hu said.
Dr. Hu pointed to SMA to illustrate the power and potential of newborn screening working hand-in-hand with the development of new treatments. SMA is a neurodegenerative disorder caused by mutations in SMN1, which encodes survival motor neuron protein (SMN).7 Deficiencies in SMN results in loss of motor neurons with muscle weakness and, often, early death.7A pilot study, on which Dr. Chung was the senior author, used both biochemical and genetic testing of close to 4000 newborns and found an SMA carrier frequency of 1.5%. One newborn was identified who had a homozygous SMN1 gene deletion and two copies of SMN2, strongly suggesting the presence of a severe type 1 SMA phenotype.8
At age 15 days, the baby was treated with nusinersen, an injection administered into the fluid surrounding the spinal cord, and the first FDA-approved genetic treatment for SMA. At the time of study publication, the baby was 12 months old, “meeting all developmental milestones and free of any respiratory issues,” the authors report.
“Screening for SMA — which was added to the RUSP in 2018 — has dramatically transformed what used to be the most common genetic cause of death in children under the age of 2,” Dr. Chung said. “Now, a once-and-done IV infusion of genetic therapy right after screening has transformed everything, taking what used to be a lethal condition and allowing children to grow up healthy.”
Advocating for Inclusion of Diseases With No Current Treatment
At present, any condition included in the RUSP is required to have a treatment, which can be dietary, surgical/procedural, or an FDA-approved drug-based agent. Unfortunately, a wide range of neurodevelopmental diseases still have no known treatments. But lack of availability of treatment shouldn’t invalidate a disease from being included in the RUSP, because even if there is no specific treatment for the condition itself, early intervention can still be initiated to prevent some of the manifestations of the condition, said Dr. Hu.
“For example, most patients with these diseases will sooner or later undergo seizures,” Dr. Hu remarked. “We know that repeated seizures can cause brain damage. If we can diagnose the disease before the seizures start to take place, we can put preventive seizure control interventions in place, even if there is no direct ‘treatment’ for the condition itself.”
Early identification can lead to early intervention, which can have other benefits, Dr. Hu noted. “If we train the brain at a young age, when the brain is most receptive, even though a disease may be progressive and will worsen, those abilities acquired earlier will last longer and remain in place longer. When these skills are acquired later, they’re forgotten sooner. This isn’t a ‘cure,’ but it will help with functional improvement.”
Moreover, parents are “interested in knowing that their child has a condition, even if no treatment is currently available for that disorder, according to our research,” Dr. Chung said. “We found that the parents we interviewed endorsed the nonmedical utility of having access to information, even in the absence of a ‘cure,’ so they could prepare for medical issues that might arise down the road and make informed choices.”9
Nina Gold, MD, director of Prenatal Medical Genetics and associate director for Research for Massachusetts General Brigham Personalized Medicine, Boston, obtained similar findings in her own research, which is currently under review for publication. “We conducted focus groups and one-on-one interviews with parents from diverse racial and socioeconomic backgrounds. At least one parent said they didn’t want to compare their child to other children if their child might have a different developmental trajectory. They stressed that the information would be helpful, even if there was no immediate clinical utility.”
Dr. Nina Gold
Additionally, there are an “increasing number of fetal therapies for rare disorders, so information about a genetic disease in an older child can be helpful for parents who may go on to have another pregnancy,” Dr. Gold noted.
Dr. Hu detailed several other reasons for including a wider range of disorders in the RUSP. Doing so helps families avoid a “stressful and expensive diagnostic odyssey and also provides equitable access to a diagnosis.” And if these patients are identified early, “we can connect the family with clinical trials already underway or connect them to an organization such as the Accelerating Medicines Partnership (AMP) Program Bespoke Gene Therapy Consortium (AMP BGTC). Bespoke “brings together partners from the public, private, and nonprofit sectors to foster development of gene therapies intended to treat rare genetic diseases, which affect populations too small for viable commercial development.”