Making Early Diagnosis of Inherited Diseases a Clinical Reality

article image

Gene and cell therapies have curative potential for some inherited genetic diseases, but technologies for rapid screening and diagnosis of genetic variants are a prerequisite. An excerpt from our recent interview with Stephen Kingsmore, who is at the forefront of making pediatric genomic testing and newborn screening universal and accessible.

The FDA’s March 2024 approval of a gene therapy for metachromatic leukodystrophy (MLD), a fatal genetic disorder that destroys children’s neurons, is the latest example of how advances in gene and cellular therapies are upending treatments for a select group of rare, inheritable genetic diseases.

The therapy, Lenmeldy, can be remarkably effective, enabling some children who have the disease to lead normal lives. But it comes with a hefty price tag—$4.5 million—and doesn’t reverse damage caused by the disease. If it is going to have value, it needs to be given to children as early as possible, even before symptoms appear.

Making sure that rapid identification is a routine part of clinical care is the goal of Stephen Kingsmore, MD, DSc. An immunologist by training, the president and CEO of Rady Children’s Hospital Institute for Genomic Medicine in San Diego years ago began focusing on an entirely different area of medicine—pediatric genomic testing and newborn screening. His group at Rady twice set the world record for the fastest genetic diagnosis of a child through rapid whole genome sequencing (rWGS)—marking just 13.5 hours from sample collection to diagnosis of a rare disease.

More recently, the group has been studying the power of rWGS for newborn screening and optimizing ways to educate providers on the nuances and value of the test results. Two of Kingsmore’s recent projects have the potential to significantly affect how we identify children with rare genetic diseases. Beginning in 2018, Project Baby Bear, funded by California, sought to demonstrate that accelerated diagnosis of critically ill newborns through rWSG could save money and change medical decisions, improving outcomes. Results were published in the American Journal of Human Genetics in 2021 and showed that sequencing of 178 newborns saved California’s Medi-Cal program a net of nearly $3.7 million. The study found that rWGS had a 43% diagnostic rate, affecting 76 babies, and, of those, 55 had a change in care as a result of the testing. This work led to policy and legislative changes, which have made rWGS mandatory for critically ill children in some states.

Kingsmore and others have also been aggressively working to make rWGS screening of healthy newborns universal. Biochemical measures that are read by mass spectrometry have been available since the 1960s for newborn screening for a handful of genetic diseases. The US government’s Recommended Uniform Screening Panel (RUSP) recommends it be done for 35 core disorders. Between 2006 and 2022, these tests generated more than 6,400 positive results. Still, this number is a drop in the bucket, given scientists estimate there are roughly 7,200 to 10,000 genetic diseases, and hundreds of targeted therapies have been approved or are in clinical trials for some of them. If Kingsmore has his way, rWGS will expand those RUSP guidelines to hundreds.

To lay the scientific foundation for these goals, in 2022, Kingsmore’s team organized BeginNGS, a consortium that is studying rWGS as a newborn screen for more than 409 treatable early-onset inherited diseases, a number that will fluctuate and ultimately expand as scientific research about inherited diseases advances. The goal has been to identify these children from among healthy babies and intervene quickly, before diseases progress. And solutions do not always require experimental or wallet-busting drugs. In many cases, if the pathological variant is detected, the interventions are straightforward and well known and can be as simple as changes in diet, the use of vitamin supplements, or avoidance of certain medications.

With Phases I and II completed, the consortium recently began a Phase III study, which will enroll 10,000 babies by mid-2025, with the longer-term goal of testing hundreds of thousands of babies. The study will explore the feasibility, utility, and cost acceptance of a soup-to-nuts approach to rWGS, pairing parental consents with appropriate confirmatory testing, diagnosis, and management. The goal is to make rWGS universal and accessible to community physicians by reducing the cost per test, currently about $2,000, and offering clinical support services through its Genome-to-Treatment virtual acute care management strategy. These can only be accomplished if these are high-volume processes that are almost entirely automated.

Read our full interview with Kingsmore here.

Articles from Wendy Diller:


VUZE Medical: Software-Based Guidance for MIS Spine Surgery and Beyond

Surgeons have been satisfied with short-segment X-ray-guided interventions for decades, but their needs are changing as more procedures move to minimally invasive, outpatient and ambulatory settings. VUZE Medical has developed a software-based guidance system for MIS spine surgery that meets the market’s changing needs by adding capabilities to the X-ray guidance already in place.

Read Article