When it comes to brain disorders, the standard method used to find a drug for children is upside down, says Donna Ferriero, MD, chief of pediatric neurology at Lucile Packard Children's Health Services at UCSF. New drug therapies typically are designed for adults and tested on them. Studies to find out if the drug can be used for children usually are limited to finding the right, scaled-down child-size dose.
It is time that children got their own treatments, Ferriero writes in an editorial in the December 1998 issue of Current Opinion in Pediatrics. She says that scientists now have enough information about young children's developing brains to start looking for appropriate therapies specifically targeted at childhood neurological disorders.
Her editorial introduces five scientific articles on different brain disorders, bound together by new knowledge about how they cause brain injury. An international conference slated for December 8-9 in Washington, D.C. will focus on interventions that might work against one of the most common causes of brain damage, perinatal asphyxia, where a newborn is accidentally deprived of oxygen and blood flow during birth.
The scientists are spurred partly by the history of adult drugs used on children -- some are ineffective, some have unexpected results, some even cause the opposite effect that they have in adults. But Ferriero says the most compelling reason for child-specific treatment is the growing body of evidence that a young child's nervous system is not a miniature version of an adult's. From before birth throughout the first decade of life, the brain continues to develop and change, as some neurons grow and make connections and others are pared away. When children's brains are damaged by a disease or an accident, the effect can be widespread, because the injury can alter a whole stage of brain development.
That also means that drugs must be designed to avoid damaging the developing brain. An ideal drug would succeed by saving a child's brain cells, without hindering further stages of brain organization and development. And different stages might require different therapies -- one type of drug for premature infants, something else for a newborn or a toddler.
This is where science comes in. "To develop appropriate therapies for the developing nervous system gone awry, we need more information about what goes wrong," Ferriero says. "It will take the combined efforts of many teams of investigators throughout the world, studying genes, cells, animals and humans, to provide the basis for new treatments specifically for children."
Ferriero is director of the National Institutes of Health funded Neonatal Brain Disorders Center at UCSF, where her own research on oxygen/blood flow deprivation is one of many projects focussing on protecting the brains of newborn babies. Researchers in her lab study oxygen deprivation from several angles, ranging from genetic and in-vitro cell studies to efforts to improve diagnosis and care for babies whose brains have been deprived of oxygen. Her research group also is working on an animal model for hypoxia-ischemia that will allow them to test not only whether infant rats survive an incident of asphyxia but whether they grow up with the ability to learn and remember. "It is not enough to save brain cells," Ferriero says. "We have to make sure those neurons continue to develop and function properly."
Other labs are working on a range of childhood brain disorders. Ferriero's Current Opinion editorial serves as an introduction to the following:
-Yasmin Khakoo and Myrna Rosenfeld of Sloan-Kettering Memorial Hospital, New York, report on mechanisms in the cell cycle of the developing brain including ideas that might be useful to turn off the rapid growth of brain tumors.
--Pierre Gressens of Hopital Robert Debre, Paris, describes how neuroimaging techniques have provided clues to brain malformations that run in families. That has enabled researchers to develop animal models that may show how the genes that command brain development may be influenced by environmental factors like caffeine.
--Isabelle Rapin of Albert Einstein College of Medicine, New York, shows how functional and structural images of brain abnormalities that are linked to language disorders make it possible to sort out the contributions of inheritance versus injuries like asphyxia and seizures.
--Christopher Giza and Raman Sankar of UC - Los Angeles describe how the genetic underpinnings of childhood epilepsies may lead to new, highly specific treatments for seizures -- and also may show why some children develop epilepsy after a brain injury, and others do not.
--Nicola Robertson and A. David Edwards of Hammersmith Hospital, London, discuss the potential difficulties with treating perinatal asphyxia with the same therapies that have proved successful for adult stroke.
Ferriero says that it will take more basic science to translate the research from labs like these into treatments that help children. It also might take a system such as the one proposed a year ago by Jerold Lucey, MD editor of the journal Pediatrics. He suggested a coordinated network of doctors and researchers from many disciplines, working like the NIH's Children's Cancer Group. This network would coordinate nationwide research and clinical trials aimed to eliminate brain damage among newborns.
However, before clinical trials could go forth on any scale, drug companies also would have to make a commitment to test new treatments and seek approval from the Food and Drug Administration. Yet out of thousands of drugs currently in development in the U.S., fewer than 150 are aimed at children's diseases, says Ferriero. Only eight are being tested for a childhood brain disorder, epilepsy.
"To get a start on drug development for hypoxia-ischemia in newborns, it almost seems as if this issue would have to become personal for someone in program development at a pharmacuetical company," Ferriero said. "Unless someone knows a family whose child must live with a profound loss of brain function, it may not be clear how urgent this issue is."
NOTE TO REPORTERS: Perinatal asphyxia will be featured at the Hot Topics in Neonatology conference, Dec 6 - 8, 1998 in Washington DC at the Hyatt Regency Capitol Hill. The program chair is Jerold Lucey MD, editor of the journal Pediatrics
Alice Trinkl, News Director
Source: Janet Basu (415) 476-2557
E-mail: janbasu@itsa.ucsf.edu