HOW CAN WE HELP YOU? Call 1-800-TRY-CHOP
Lifespan Research Aims to Improve Health From Gestation to Adulthood
Powerful Gene-editing Tool
William Peranteau, MD, an investigator in the Center for Fetal Research, and a pediatric and fetal surgeon in the Center for Fetal Diagnosis and Treatment, received a highly competitive grant award that will allow his team to explore the use of prenatal CRISPR-mediated gene therapy in congenital disorders. He received $1.5 million over a five-year period through the NIH Director’s New Innovator Award.
Dr. Peranteau’s research focuses on using CRISPR — a powerful gene-editing tool that harnesses an enzyme to cut and paste genetic instructions at a precise location in a DNA sequence — to cure or reduce the severity of genetic disorders before birth. He emphasized that much more work needs to be done prior to considering clinical application.
In related research, Dr. Peranteau, also an assistant professor of surgery in the Perelman School of Medicine at the University of Pennsylvania, and collaborators at Penn were successful working with mouse models to correct a harmful mutation before birth by using CRISPR-mediated gene editing. They thwarted a lethal lung disease, surfactant protein deficiency, in which death occurs within hours after birth. This proof-of-concept study appeared in Science Translational Medicine.
“The ability to cure or mitigate a disease via gene editing in mid-to-late gestation before birth and the onset of irreversible pathology is very exciting,” Dr. Peranteau said in a press release at the time of publication. “This is particularly true for diseases that affect the lungs, whose function becomes dramatically more important at the time of birth.”
The New Innovator Award will allow his team to explore prenatal CRISPR gene editing in other congenital disorders.
New Genetic Signature
CHOP researchers gained insights into genetic differences between latent autoimmune diabetes (LADA) in adults and type 1 diabetes (T1D) in children that may be diagnostically useful, according to study leader Struan Grant, PhD, co-director of the Center for Spatial and Functional Genomics at CHOP and the Daniel B. Burke Endowed Chair for Diabetes Research. The new genetic signature may allow clinicians to diagnose LADA using a genotype array instead of a complex and expensive autoantibody screening.
LADA, also referred to as type 1.5 diabetes, shares characteristics with both T1D and type 2 diabetes (T2D); however, from a genetic perspective, CHOP researchers previously found LADA has more in common with T1D than with T2D. The new findings, published in the journal Diabetes Care, took a deeper dive into LADA’s distinguishing differences, opening the door to more straightforward diagnostic tests and improved responses to appropriate treatments.
One of those differences identified by the research team is that they did not observe genetic associations with the major histocompatibility complex (MHC) in patients with LADA. MHC is a highly variable region of the genome that helps drive the immune system and is implicated in T1D.
“This suggests that these MHC class associations may be a genetic discriminator between LADA and childhood-onset T1D,” said Diana Cousminer, PhD, a geneticist at CHOP and a joint-first author of the study. “The next step is to look at this association in different ethnicities, particularly African ancestry, where the prevalence of adult-onset diabetes can be significantly higher in certain parts of the world.”
Results from the “MOMS2: Follow-up of the Management of Myelomeningocele Study,” published in Pediatrics, showed significant physical and emotional benefits in school-age children who received corrective surgery in the womb for MMC, the most severe form of spina bifida.
“It is extremely gratifying to see that the positive results from the initial MOMS trial endure into childhood,” said N. Scott Adzick, MD, MMM, CHOP’s Surgeon-in-Chief, who first performed fetal surgery to repair spina bifida in 1998 at CHOP’s Center for Fetal Diagnosis and Treatment. “Fetal surgery is a complex and serious procedure and should only be done by experienced teams. Research needs to continue to refine the technique in a way that will improve outcomes even further.”
Although there was no significant difference in overall adaptive behavior or cognitive benefits between children who had prenatal surgery for spina bifida compared to children who had surgery after birth, motor function and quality of life were better among children in the prenatal surgery group. Long-term gains included improved mobility and independent functioning in school age children. Walking unassisted, better gross and fine motor skills, improved bladder and bowel control, and fewer surgeries for shunt placement and revision were among the benefits. In addition, the children and families in the prenatal group reported less stress on the family overall.
In 2011, results of the original landmark study “MOMS: Management of Myelomeningocele Study” also led by Dr. Adzick, appeared in the New England Journal of Medicine.
Filling a Knowledge Gap
The Genome to Mental Health consortium is a new collaboration between researchers at CHOP and 13 institutions worldwide to study the link between rare genomic disorders and psychiatric and developmental conditions. Donna McDonald-McGinn, MS, LCGC, director of the 22q and You Center at CHOP, is leading the initiative at CHOP.
“This project is funded to not only examine the chromosome 22q11.2 deletion, but also 22q11.2 duplication, which is highly associated with autism, and other copy number variants, such as 16p11.2 deletion and duplication,” said McDonald-McGinn, who is also a clinical professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania. “These conditions are the result of extra or missing pieces of chromosomes, leading to extra or missing copies of genes and resulting in behavioral differences.”
The Genome to Mental Health researchers will be examining multiple phenotypes, including psychosis, anxiety, ADHD, depression, and autism, to determine their prevalence and to identify specific genes within the copy number variants that may contribute to how patients present and how the longitudinal disease course will progress. Ultimately, their aim is to inform early detection of these conditions and their associated features, as well as to identify biologic targets that could be used to develop novel therapeutics for these patients.
A set of simple questionnaires can help clinicians and families evaluate better the quality of life of people diagnosed with autism spectrum disorder (ASD), according to a study led by CHOP researchers. The newly developed tool, PROMIS Autism Battery – Lifespan (PAB-L), is designed for children, adolescents, and adults on the autism spectrum. It focuses on five domains: subjective well-being, relationships, emotional distress, health, and adulthood.
A total of 912 participants completed the tool’s surveys online. The study measured feasibility, and participants reported that the survey was easy to understand, covered important topics, and may even change the way an individual or parent manages their autism support programs or clinical care based on the results.
“This study demonstrated that assessing quality of life among patients of different ages and genders is possible, and that it’s meaningful,” said Judith S. Miller, PhD, a psychologist in the Department of Child and Adolescent Psychiatry and Behavioral Sciences, a senior scientist and training director in the Center for Autism Research at CHOP, and senior author of the study. “We believe that these findings provide an important foundation to answer some very important questions about how to support the quality of life for people with autism, including those who have been historically underrepresented in clinical research.”
The study appeared in Autism Research.