Stanford ChildX 2018: Big ideas for little patients

PLOS Medicine Associate Editor Linda Nevin shares some highlights from ChildX, a cross-disciplinary science, medicine, public policy and healthcare symposium on research developments and opportunities for improving pediatric care.

Stanford faculty are striking for their willingness to stroll across a quad, skirt a construction site or wade through a fountain to share ideas with colleagues and visitors. Late last week at ChildX, a cross-disciplinary science, medicine, public policy and healthcare symposium hosted by the institution’s Child Health Research Institute, twenty Stanford and visiting experts converged on Stanford School of Medicine’s Paul Berg Hall in this tradition. An audience comprising clinicians, researchers, students and one PLOS Medicine editor drank it all in as the speakers shared their insider perspectives and ‘what’s next’ insights. Several ‘wow!’ stories deserve special mention.

1) CRISPR gene editing dominates in the press, but antisense therapy is already in the clinic—and working miracles for infants with spinal muscular atrophy.

Children with spinal muscular atrophy (SMA) type 1 have severe neuromuscular impairment and do not naturally live past age 2. The condition is autosomal recessive, which means that replacement of the gene, transcript or protein could be curative. In three recent trials, participants with SMA were shown to benefit from therapies (one an antisense oligo [ASO] that promotes proper splicing of a paralog, the other a viral-borne replacement gene) that promote increased production of the missing protein. Stanford neurologist John W. Day presented his and his collaborators’ findings from their trials of the ASO therapy, in which intrathecal injection of an ASO (nusinersen) restores proper splicing of a mostly nonfunctional paralog (SMN2) of the mutated gene (SMN1).

Here are the recent trial publications from the NEJM.

• Finkel et al: ASO therapy for infantile-onset SMA, phase 3 trial (2017)
• Mendell et al: gene replacement therapy for infantile-onset SMA, phase 1-2 trial (2017)
• NEJM Editorial on the trials
• An explanatory NEJM Quick-Take
• Mercuri et al: ASO therapy for later-onset SMA, phase 3 trial (2018)

As nusinersen appears to have better efficacy when applied early, Dr. Day and colleagues are working to have the SMN1 mutation added to newborn screening panels.

The ASO and viral approaches have not been compared head-to-head, and as of now, neither provides a cure. The anticipated cost is $750,000 for the first course of nusinersen, with repeated courses required (likely throughout life). As for many developments presented at ChildX, availability of a therapy for SMA will sort families’ outcomes by socioeconomics. Payment policies applied to SMA therapy may set important precedent, as there are dozens of ASOs in development and in clinical trials, including trials in Huntington disease and in ALS.

2) We’re still learning how analysis of cell-free nucleic acids can help the littlest patients.

In his keynote talk, Stanford biophysicist Stephen Quake discussed varied developments—in prenatal diagnostics, care of organ transplant recipients, infection monitoring, immunologic signaling and the biology of the microbiome—stemming from his pioneering work in single-molecule sequencing of circulating cell-free DNA (cfDNA). His more recent work uses cell-free RNA (cfRNA), which reveals crosstalk within the genome and between cohabiting genomes. Several clinicians in attendance are eagerly awaiting the output of a current Quake group project, the characterization of cfRNA communication between fetus, placenta, and mother, which may lead to prediction, better understanding, and even prevention of pre-term birth.

Here is some pediatrics-relevant cfDNA research from Stephen Quake and his many collaborators:

• Fan et al’s characterization of the fetal genome and exome (Nature, 2012)
• Khush et al’s study showing that the amount of circulating tumor cfDNA correlates with heart transplant rejection (Sci Transl Med, 2014)
• De Vlaminck et al’s diagnostic assay that monitors rejection and infection in lung transplant recipients (PNAS, 2015)
• Pan et al’s characterization of the human transcriptome and microbiome of 60 pregnant women—an approach to monitoring infections and immune responses during pregnancy (Clin Chem, 2017)

Further developments to look for, as described in Dr. Quake’s talk, include these:

• According to cfDNA sequencing of the microbiome, the distribution of viral phyla (but not bacterial phyla) has a dramatic response to immunosuppressant and antiviral drugs
• cfDNA sequencing may be useful for 1-step identification of an infective pathogen
• Fetal age (to the day) can be determined from the distribution of placental, immunologic, and fetal cell-free RNA (cfRNA) in maternal plasma—a potential boon for obstetric practice in low-resource settings

3) Behavior change may or may not check the childhood obesity epidemic, depending on the role of infection.

The cause of the obesity trend is debated, but its impact isn’t. In a “Childhood Obesity Epidemic: Novel Solutions” session, moderator and Stanford pediatrician Tom Robinson warned us that “[t]his may be the first generation that has a shorter lifespan than the previous generation, mainly due to the obesity epidemic.” According to Dr. Robinson, obesity-related medical care costs are estimated to be greater than $150 billion annually—not including costs due to lost productivity. In his own and others’ work, Dr. Robinson finds that interventions intended to reduce sedentary screen time among children are more effective than interventions aimed at dietary choices.

Following this, Stanford infectious disease specialist Julie Parsonnet took the stage and shared descriptive evidence consistent with a more intractable cause for the obesity epidemic—the decline of infectious disease. Based on historical data on human temperatures, and recent data on immune repertoires among children in different global settings, she suspects that in modern high-income countries we bear fewer infections, run cooler temperatures, and therefore burn fewer calories during childhood than our forebears and our brethren in low-income countries. Unless we’d like to reintroduce widespread measles (we don’t, she noted), we may need to content ourselves with a different physique—screen time and donuts notwithstanding. She is continuing to explore relationships between infection and obesity in the Stanford Outcomes Research in Kids (STORK) study, which is prospectively testing the hypothesis that children with more fevers gain less weight as they grow.

Stanford Medicine’s SCOPE blog provides a synopsis of the full “Childhood Obesity Epidemic” panel in their post.

Other keynote speakers at ChildX were Stanford psychologist Carol Dweck (audience question: How old is too old for a growth mindset? Answer: You’re never too old), Johns Hopkins ethicist Jeffrey Kahn on quandaries in mitochondrial replacement therapy (the “three-parent baby” assisted reproduction technique currently approved in the U.K., but not in the U.S.), and Stanford economist Raj Chetty on big data’s lessons on improving economic opportunities for children—a talk rendered in sharp relief among many tales of costly, state-of-the-art care.

Many thanks to Stanford pediatricians Heidi Feldman and David Cornfield for organizing. The recorded talks are available here.

Feature image credit: Linda Nevin