CHICAGO – In a paper published this week in the American Journal of Human Genetics, collaborators led by the Rady Children's Institute for Genomic Medicine (RCIGM) formally spelled out plans to improve detection and treatment of rare hereditary pediatric diseases through rapid whole-genome sequencing (rWGS).

Called BeginNGS — standing for Newborn Genomic Sequencing and pronounced "beginnings" — the program aims to make rapid WGS a standard of care for newborns by implementing Genome-to-Treatment (GTRx) , a virtual acute management guidance system to inform treatment of hundreds of hereditary pediatric diseases. Many of the same authors of the new article described GTRx in a paper that appeared in Nature Communications a month ago.

In the newly published paper, they called rapid WGS for newborn screening "attractive" and "feasible for hundreds of severe, early childhood-onset genetic disorders that progress rapidly if untreated and have effective therapies." 

San Diego-based Rady Children's Hospital publicly launched BeginNGS in June with partners including Inozyme Pharma, Alexion Pharmaceuticals, AstraZeneca, Illumina, TileDB, Fabric Genomics, Genomenon, Travere Therapeutics, and several patient advocacy groups. RCIGM President and CEO Stephen Kingsmore previewed the plan at the Bio-IT World Conference & Expo in May.

Rady developed GTRx in collaboration with Illumina, Alexion, RPRD Diagnostics, Rancho Biosciences, Genomenon, Epam Systems, and several other research centers. Those partners have been helping Rady curate genes for specific, treatable rare diseases.

Genomenon CEO Mike Klein explained that GTRx is meant to build a database of treatments around genetic diagnoses that potentially can inform physicians in community settings who may have never seen specific rare diseases.

For GTRx, Genomenon is precurating genes and variants so the information is available as soon as sequencing results are ready.

The authors of the new AJHG article said that the number of genetic diseases examined by newborn screening has lagged innovation in genomics or therapeutics. BeginNGS effectively flips genetic medicine for rare diseases on its head by precurating variants and starting with lists of therapeutics rather than genes.

While working on GTRx, Kingsmore and his RCIGM colleagues realized that those who recommend gene panel tests in newborn screening "started at the wrong end," he said. "We said that if we start with the treatments, that guides us as to what the genes need to be." That is what BeginNGS is about.

Standard heel pricks for newborns are run through biochemical assays that look for perhaps 30 to 60 conditions, depending on the jurisdiction, according to Klein. As currently constituted, GTRx contains 421 disorders, 333 genes, and 1,527 interventions.

The BeginNGS consortium hopes to add several thousand genes in 2023. "I expect that probably by the end of next year, we'll have gotten … most of the clinical exome precurated," Klein said.

Genomenon's Mastermind database contains more than 18 million variants, and Klein noted that the company is working on curating the entire human genome, an effort expected to be complete by the end of 2024.

"We'll put that [information] at the fingertips of clinicians and pharma researchers who are developing precision medicine," he said. "Having a lookup table of every variant is going to play a key role in doing newborn screening."

BeginNGS is essentially a pilot of the GTRx database. "Can you show efficacy in doing this newborn screening, and can you get it to be cost-effective, can you have a low false-positive rate, and can we save babies' lives?" Klein asked in stating the goals of the program.

Artificial intelligence helps data scientists sort through medical literature to match knowledge with variants, then expert curators review what the technology finds for accuracy and adherence to American College of Medical Genetics and Genomics guidelines. "We present the findings for [clinicians] to make the final diagnosis," Klein said.

Kingsmore called medical literature "a complete mess" for the rare diseases included in GTRx.

"Generally in medicine, you understand exactly what to treat a patient with when you make a diagnosis," Kingsmore said. But with rare diseases, treatments might be off-label uses of approved drugs or compounds still in clinical trials.

"What's the point in diagnosing a baby with a genetic disease if the doctor doesn't know what to do with that information?" Kingsmore said. "GTRx is our effort to go beyond diagnosis" to unravel what Kingsmore and colleagues have dubbed the "therapeutic odyssey," though that term does not appear in the AJHG article.

"You don't [just] send the doc a diagnostic report," Kingsmore explained. "You send the doc a diagnostic report with a hyperlink designed for them so that they will know which subspecialists to consult, which medications to start, and not just the list of medications, but the things that they need to know" such as efficacy, timing, and contraindications.

Kingsmore said that it should take about 20,000 babies to prove the clinical utility of GTRx and 200,000 to demonstrate that the strategy is cost-effective, but the BeginNGS consortium is aiming to sequence 1 million infants to diversify the dataset as much as possible.

Kingsmore said that it is important to include pharma and biotech firms in the consortium to give them the incentive to develop new therapies for rare diseases. Indeed, the AJHG article invited other groups to participate "to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness," as the current iteration of BeginNGS is considered a prototype.

"There is so much work to be done, and it's so complex that it requires a consortium to agree to be precompetitive," Kingsmore said. "We need to get this over some critical hurdles, and the only way to do that is to work together and form a consortium."

While BeginNGS aims to lessen the time to diagnosis and therapy, it is also intended to inform clinicians of the risks of ordering more radical and invasive interventions too soon, such as hematopoietic stem cell transplants for severe immune deficiency disease, heart transplants for certain cardiomyopathies, or defibrillator implantation for cardiac arrhythmias, according to Kingsmore. "I have to be sure that the benefits of putting [a defibrillator] in a kid's chest outweigh the fact that it will go off periodically and give them a massive shock that's going to freak them the heck out," he said.

In one test case of BeginNGS, the partners will use rapid WGS to identify infants affected by ENPP1 deficiency and ABCC6 deficiency. Inozyme is developing a novel therapy, INZ-701, currently in Phase I/II clinical trials, to treat the rare genetic diseases of ENPP1 and ABCC6 deficiencies, which can result in abnormal mineralization in blood vessels, soft tissues, and bones.

Catherine Nester, VP of physician and patient strategies at Boston-based Inozyme, explained that abnormal mineralization has a mortality rate of 50 percent in the first six months of life.

"Because it's rare, it does get missed quite a bit," Nester said. Sequencing will catch the gene mutations that cause the condition. If INZ-701 eventually gets approval, infants with the rare deficiency would be able to start on treatment nearly as soon as the rapid sequencing is complete.

Inozyme has data on an adult population with ENPP1 and ABCC6 deficiencies showing that the compound can raise inorganic pyrophosphate levels, and the company will start pediatric studies before the end of 2022.

"The whole point of the newborn screening program is that it will be at a national level," Nester said. Right now, there are variations from state to state, and it can take years to have novel diseases added to the US Department of Health and Human Services' Recommended Uniform Screening Panel for newborn screening.

"This would … be a game changer," Nester said. "If you have a more efficient way to find the patients, then it makes developing drugs and enrolling studies much easier."

Kingsmore said that the cost of rapid WGS and analysis needs to come down to about $200 per test for BeginNGS to be viable. Right now, each prototype test costs closer to $2,000.

"The prerequisites for inexpensive NBS-rWGS are performance at massive scale and near complete automation," Kingsmore and colleagues wrote in the journal article.

"This is a knowledge and information problem," Kingsmore told GenomeWeb. "The sequencing piece is easy." The analysis and AI are not so easy, but they are central to increasing the efficiency of rare disease diagnosis.

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