Many scientists trace their childhood inspiration to the towering skeletons of dinosaurs that still reign over the regal lobbies of the American Museum of Natural History, myself included. But “natural history” has a different meaning in medical research, especially in evaluating new treatments for rare diseases. Searching PubMed under “natural history study” turns up a curious 75,000 or so entries, including rare diseases and museum taxidermy.
A medical natural history study looks at how a disease unfolds over time, in real patients, to provide a point of comparison and variability for evaluating new treatments. A neurologist, for example, might know how to handle an otherwise healthy child with ADHD; a youngster with ADHD as part of Sanfilippo syndrome presents a different clinical picture. A natural history study provides an idea of what to expect.
Here’s an example: Rett Syndrome. It affects 1 in every 10,000-15,000 girls and results from a mutation in an X chromosome gene, MECP2. The gene controls several other genes, so a mutation triggers a cascade of effects. Girls seem okay in infancy and early toddlerhood, but then development slows. A telltale sign is a distinctive holding and wringing of the hands. The girls develop problems walking, have seizures, and may have autism and/or intellectual disability. But behavior was harder to describe. So a recent natural history study examined “internalizing” (such as anxiety and social withdrawal) and “externalizing” (aggression and self-abuse) behaviors in 861 girls with Rett syndrome, and found that internalizing behaviors were common, externalizing ones not. Investigators can use the distinction in evaluating new treatments.
Making a List
A natural history study begins with a disease registry – signing up patients. When parents receive a diagnosis of an extremely rare disease in their child, joining or starting a disease registry is an early step to funding research. Having a registry can help to avoid ultimately denying treatment to some clinical trial participants to provide a control group.
Shire, “the global leader in rare disease,” recently announced multi-year support for ten new rare disease registries through NORD’s IAMRARETM Registry Program, targeting rare disease communities that don’t yet have a formal patient advocacy group.
A Benchmark to Track Progress
Natural history studies have been the backbone of clinical trial planning for many years. Today, with new types of treatments adding years to patients’ lives – from gene therapy to antisense treatments to immunotherapies to enzyme-based interventions to CAR-T approaches – knowing what to expect without treatment is more important than ever.
Sometimes the course of a condition is unmistakable and hardly needs sophisticated tracking. That’s the case for Corey Haas, who recently turned 18 and is the main subject of my gene therapy book. He’s just returned from his 10-year follow-up at Children’s Hospital of Philadelphia, where he was one of the first, and the youngest at the time, to receive gene therapy for a form of inherited visual loss caused by mutation in the RPE63 gene.
Enough is known of the natural history for Corey’s condition that success is obvious: he sees! Without the intervention, he would have been nearly sightless by now. Another astonishing success illuminated by natural history studies is spinal muscular atrophy, which responds to gene therapy and an antisense drug – otherwise children do not survive.
For the parents of kids who’ve had pioneering therapies for conditions more difficult to assess than vision, efficacy is harder to pinpoint.
Is Hannah Sames’ growing strength due to the gene therapy she had for giant axonal neuropathy two years ago, or to many hours of occupational and physical therapy? If a boy who’s taken the Duchenne muscular dystrophy drug FDA-approved two years ago yesterday begins to walk 2 feet more on a timed treadmill test than he did before taking the drug, is it an improvement, or consistent with the variability of how children walk in the natural history study? A few extra steps might fall within the realm of what’s possible for that disease among all patients, yet be extraordinary for him. And parents of kids with neurological conditions are well aware that optimism can cloud observations of improvements.
When Technology Extends “Natural” History: Huntington Disease and Pompe Disease
Technology may be able to extend the limits of natural history investigations for rare diseases at both ends: using biomarkers to identify a disease presymptomatically, and tracking disease progression after new treatments extend survival into a new realm.
Efforts to identify early Alzheimer disease are often reported in the news, because so many people are affected. Rare diseases, not so much. That’s why a paper in last week’s Science Translational Medicine caught my attention: “Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease.”
The first indications of HD are easy to dismiss, even for those who know the disease is in the family: mild confusion in making selections or in following familiar directions; sudden inexplicable irritability or anger; clumsiness. Lisa Genova’s excellent 2015 novel Inside the O’Briens, which I reviewed here, captures the early signs well. (Her more recent book about ALS, Every Note Played, is even better.)
A reliable biomarker for about-to-begin HD would not only validate patients’ observations, but perhaps enable them to enter natural history studies to document early changes. Findings would then be incorporated into clinical trials to assess early or even preventative treatments.
The new study, led by investigators from University College London (UCL), looked at levels of two proteins in blood plasma and in cerebrospinal fluid. Huntingtin (Htt), the direct product of the mutant gene, has characteristic extra glutamines corresponding to triplet repeats at the start of the gene, the more repeats the earlier the onset. The second protein, neurofilament light (NfL), is released in bits as neurons degenerate.
Forty of the 80 participants in the study had HD symptoms, 20 knew from genetic testing that they were “premanifest,” and the other 20 were controls who didn’t have the mutation.
Levels of both biomarkers were highest in patients with HD, and NfL levels in the blood had the strongest association with clinical severity. Levels of NfL in cerebrospinal fluid predicted brain volume better than the biomarker in blood or extended Htt in cerebrospinal fluid. That’s important because past studies using imaging noted shrinking brains before diagnosis based on symptoms.
Abnormal Htt distinguished individuals who did not have a mutation from those who did – not surprising. More tellingly, concentration of NfL in cerebrospinal fluid and blood enabled the more subtle distinction of premanifest from people with symptoms. The researchers conclude that these biofluid markers are meaningful enough to incorporate into clinical trial designs to test new drugs.
Timing is terrific, because a drug for HD is about to enter phase 3 clinical trials. Recently renamed RG6042 (formerly called IONIS-HTTrx), the drug is an antisense oligonucleotide – a bit of DNA-like nucleic acid that clamps down on and effectively silences the extra repeats. Stay tuned.
For Pompe disease, a treatment has been so successful that it revealed what would happen if a deadly disease was rendered less so.
When enzyme replacement therapy extended survival beyond infancy for this glycogen storage disease that gloms up muscle fibers, children who’d been improving once again required mechanical ventilation. Why? As their very enlarged hearts had shrunk thanks to the enzyme replacement, burden fell onto the phrenic nerves to the diaphragm, impairing lung function. That wasn’t known because previously no one had lived long enough to see this symptom. Perhaps some of the kids living longer can take part in an unnatural history study of sorts, to prepare for a future when this disease, and hopefully many others, will no longer be a killer.