Current CNBD Research Studies
Below is a list of current CNBD research studies. Subject tags will link you to study listings by topic.
Perturbation: Substance Use/ Abuse, Nutrition/Malnutrition, Genetic/Congenital/Developmental Disorder, Prematurity, Social/Emotional Development, Behavioral Development, Cognitive Development/Delay, Institutional Neglect/Deprivation
A Longitudinal Study Examining Three RDoC Constructs in Adolescents with Non-Suicidal Self-Injury
Kathryn Cullen, MD (Department of Psychiatry)
Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry), Karina Quevedo, PhD (Department of Psychiatry), Katie Thomas, PhD (Institute of Child Development)
Non-Suicidal Self Injury (NSSI) is a common clinical problem that cuts across many different psychiatric diagnoses, leads to severe negative outcomes, and has limited treatment options. Advancement of new interventions for NSSI is hindered by a lack of knowledge about its neural mechanisms. NSSI usually emerges during adolescence, a time period notable for significant developmental changes in brain and behavior. Characterizing the developmental trajectories of key aberrant neural systems would enhance our understanding of the pathophysiology of NSSI. The current study will be instrumental in guiding foundational knowledge necessary for creating targeted early interventions for adolescents with NSSI that are designed to promote healthy neurodevelopment.
A Marker Task of Amygdala Function in Preschool Aged Children
Jed Elison, PhD (Institute of Child Development and Department of Pediatrics)
Laura Thomas (Institute of Child Development)
The amygdala is implicated in various psychiatric and neurodevelopmental disorders. An extensive literature on animal models has characterized amygdala circuit function and its role in specific types of learning. There is also evidence that amygdala circuit function may play a unique role in learning from salient conspecifics very early in development. The bulk of our knowledge of amygdala function in humans comes from fMRI studies in children and adults and studies of patients with acquired or congenital lesions to this structure. To date, very little is known about amygdala function during the first 5 years of life, for example, whether amygdala function is developmentally invariant or whether amygdala function varies based on evolving patterns of structural and functional connectivity.The primary objective of the current study is to to characterize the degree of attentional bias to salient, biologically relevant cues presented for 24 milliseconds in ninety 3-5 year-old children and to characterize associations between attentional bias values and parent reports of reciprocal social behavior and internalizing.
A Multi-center, Randomized, Double-blind, 12-week, Parallel Group, Placebo-controlled Proof of Concept Study to Investigate the Efficacy and Safety of RO5285119 in Individuals with Autism Spectrum Disorders (ASD)
Suma Jacob, MD, PhD (Department of Psychiatry)
The primary objectives of this study are to evaluate the efficacy of 12-week treatment with RO5285119 compared with placebo in treating social communication deficits in individuals with ASD as measured by the social responsiveness scale (SRS-2) and to evaluate the safety and tolerability of 12-week treatment with RO5285119 in individuals with ASD.
A Phase I, Multicenter, Open-label, Single-dose, Dose Ranging Study to Assess the Safety and Tolerability of SB-318, a rAAV2/6-based Gene Transfer in Subjects with Mucopolysaccharidosis I (MPS I)
Chester B. Whitley PhD, MD (Department of Pediatrics)
Julie Eisengart, PhD (Department of Pediatrics), Bradley S. Miller PhD, MD (Department of Pediatrics)
Current therapies for MPS I include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT can prevent or reverse most clinical features, and is recommended for those with the severe form of the disease (Hurler syndrome [MPS IH]). However, the reported mortality rate after HSCT is 15%, and the survival rate with successful engraftment is 56%. Patients with the attenuated forms of the disease (Hurler-Scheie syndrome [MPS IHS], Scheie syndrome [MPS IS]) are treated with ERT using laronidase (recombinant human α-L-iduronidase; Aldurazyme). Laronidase has been shown to improve pulmonary function, hepatosplenomegaly, and exercise capacity. However limitations of ERT include the need for life-long treatment; development of neutralizing antibodies; inability to cross the blood brain barrier; continued cardiac, orthopedic, and ocular complications; and the inconvenience of weekly intravenous (IV) infusions.
The current proposed study uses ZFN gene-specific targeted insertion of a/6 hIDUA transgene into the liver albumin genome locus to provide long-term production of hIDUA in patients with the attenuated forms of MPS I.The objective and rationale for the proposed SB-318 investigational therapy is to remove or decrease the need for enzyme replacement therapy by in vivo genome editing.
A Phase II Multi-center, Randomized, Doubleblind, 24-Week, 3-ARM, Parallel Group, Placebo-controlled Study to Investigate the Efficacy and Safety of RO5285119 in Children and Adolescents Age 5-17 With Autism Spectrum Disorder (ASD)
Suma Jacob, MD, PhD (Department of Psychiatry)
Bradley Miller, MD, PhD (Department of Pediatrics), Rebekah Hudock, PhD (Department of Pediatrics)
To date, few studies have investigated the effect of pharmacological treatments on the social and communication deficits in ASD and no agent has received marketing approval for treating these core symptoms. Currently in the US, the only two approved medications for ASD are the atypical antipsychotics risperidone and aripiprazole, which only target irritability associated with ASD, but not core symptoms. In summary, there is no pharmacological treatment available for the social and communication deficits in individuals with ASD and as a consequence there is a high unmet medical need for effective pharmacological therapies in the treatment of core symptoms in ASD. The V1a receptor has been shown to modulate key social behaviors in both human and animal studies. Chronic administration of RO5285119 has been shown to normalize the social behavior and cognitive impairments induced in rats by prenatal valproate (VPA) exposure, an animal model that reflects some of the behavioral changes seen in ASD patients. Also, in the CNTNAP2 KO genetic mouse model of autism, V1a antagonism has been shown to rescue social impairment and repetitive behavior. In conclusion, a V1a antagonist may provide a novel and first approach to treat the core social and communication deficits in ASD.
A Phase II/III Open Label Study in MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously
Chester Whitley, M.D., Ph.D. (Department of Pediatrics)
Julie Eisengart, Ph.D., L.P. (Department of Pediatrics), Kelly King, Ph.D. (Department of Pediatrics), Bradley Miller, M.D, Ph.D. (Department of Pediatrics)
There are currently no safe or effective therapies for the treatment of MPS IIIB. Supportive therapies are used in an attempt to mitigate some of the effects of the disease. Options for management of clinical symptoms are limited, and include the use of CNS medications to control seizures, behavioral problems and sleep problems. This study provides the first treatment—intra-venous enzyme replacement therapy (ERT with investigational product called SBC-103)—for MPS IIIB. It's primary objective is to evaluate the safety and tolerability of intravenous (IV) administration of SBC-103 in subjects with MPS IIIB, who have evaluable signs or symptoms of developmental delay.
A prospective, observational, single-center study of the effects of illness and nutrition on growth and cognition in AGA VLBW preterm infants
Sara Ramel, MD (Department of Pediatrics)
Ellen Demerath, PhD (Department of Epidemiology and Community Health), Michael Georgieff, MD (Department of Pediatrics), Bridget Davern (Department of Pediatrics), Neely Miller (Department of Pediatrics), Heather Gray (Department of Maternal Fetal Medicine)
The objectives of this study are: 1) to investigate the relationship between linear growth and fat-free body mass (FFM), and subsequent cognitive function, and 2) to identify modifiable nutritional and non-nutritional factors that influence FFM accretion (and potentially cognition) during and after initial hospitalization in very low birth weight (VLBW) preterm infants. This study will test the following novel hypotheses: 1) cognitive function in VLBW preterm infants is a function of linear growth and FFM accretion; 2) both modifiable nutritional and non-nutritional factors influence FFM accretion during and after initial hospitalization in VLBW preterm infants and that these factors affect cognitive status at 24 months of age corrected for the degree of prematurity (CA); and 3) alterations in the growth hormone axis and increased pro-inflammatory cytokines mediate the relationship of slower length growth and FFM accretion to cognitive outcomes.
A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of HGT-1410 (Recombinant Human Heparan N-Sulfatase) Administration via an Intrathecal Drug Delivery Device in Pediatric Patients with Early Stage Mucopolysaccharidosis
Chester B. Whitley PhD, MD (Department of Pediatrics)
Daniel Guillaume, M.D. (Department of Neurosurgery), Kumar Belani, M.D. (Department of Anesthesiology), Julie Eisgengart, Ph.D., L.P. (Department of Pediatrics)
Mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A; MPS IIIA) is a rare, autosomal recessive lysosomal disease caused by the absence or malfunction of the gene encoding the enzyme sulfoglucosamine sulfihydrolase (SGSH—also know an heparan-N-sulfatase or sulfamidase). MPS IIIA presents in early childhood but diagnosis is often delayed until an average of 4.5 years. The central nervous system is the most severely affected organ system in patients with MPS IIIA even though GAG accumulates—and causes damage—in all tissues and organs. MPS IIIA patients have deficits in language development, motor skills, and intellectual development. They also exhibit abnormal behaviors including aggression, excess motor activity, hyperactivity, and sleep disruptions. Ultimately, a vegetative state develops with death occurring by the early teen years. The standard therapeutic approach in MPS conditions is intra-venous enzyme replacement therapy (ERT). Currently, ERT is available for MPS I, II, IV, and VI but there is none MPS III. Further, a particular problem with ERT strategies is that these macromolecules cannot cross the blood brain barrier; therefore they do not mitigate the effects of the disease in the brain. Since brain disease is of primary concern in MPS IIIA, standard ERT approaches will, in all probability, not be very efficacious. The primary objective of the study is to assess the potential clinical efficacy of recombinant human SGSH administered via a surgically placed indwelling intrathecal drug delivery device in patients with MPS IIIA. Secondary objectives include the monitoring of safety and tolerability of the drug (HGT-1410) and the effect of the product on developmental and behavioral assessment measures.
A study of intrathecal enzyme replacement for cognitive decline in Mucopolysaccharidosis I
Julie Eisengart, PhD, LP (Department of Pediatrics)
Elsa Shapiro (Departments of Pediatrics and Neurology), Igor Nestrasil, PhD (Department of Neurology)
Muccopolysaccharidosis Type I, an inborn error of metabolism due to absence of the enzyme alpha iduronidase, results in damage to many organs in the body due to accumulation of glycosamineglycans. In severe MPS I (Hurler syndrome) the central nervous system is affected but treatment with hermatopoietic cell therapy arrests the associated cognitive decline. In the attenuated forms of MPS I, our research here at the University of Minnesota has demonstrated that some patients decline in cognitive functions, only at a later date and slower rate than Hurler syndrome. The study proposed at Los Angeles Biomedical Institute at Harbor-UCLA Medical Center will examine the effects of intrathecal injections of enzyme on cognition in MPS I patients. The objectives of the study are to demonstrate the long-term safety of intrathecal enzyme replacement and to determine whether signs of cognitive impairment in MPS I can be reversed or at least stabilized.
Assessment of body composition in infants with cystic fibrosis
Elissa M. Downs, MD, MPH (Pediatric Gastroenterology, Hepatology, and Nutrition)
Sarah Jane Schwarzenberg, MD (Pediatric Gastroenterology, Hepatology, and Nutrition), Terri Laguna, MD (Pediatric Pulmonary Medicine), Sara Ramel, MD (Department of Neonatology)
In a patient with cystic fibrosis, malnutrition has been directly associated with a worse prognosis due to negative effects on activity, quality of life, and pulmonary function. Obtainment of adequate weight during childhood has been associated with decreased hospital days, fewer acute pulmonary exacerbations, and increased survival at 18 years of age. Better nutrition, along with normalized fat absorption, lead to improved pulmonary function and survival rates. Current consensus guidelines stress that early identification of deficiencies is paramount to improve overall health and allow for proper intervention; however these guidelines are based on an assessment of body weight, a number that includes both lean body mass and fat mass. At the time of cystic fibrosis diagnosis, many infants already have poor weight gain, as well as failure to thrive, and exocrine pancreatic insufficiency. In those infants with cystic fibrosis that appear well and have a normal body weight, malabsorption of fat soluble vitamins and decreased lean body mass may be present.
A decreased proportion of lean body mass with a normal weight, so called “hidden depletion,” is important to identify. Decreased lean body mass correlates with worse disease status in older children and adolescents, increases morbidity, and may not be detected with the use of body mass index alone. An increased proportion of lean body mass has been associated with improved pulmonary function. The overall goal of this research is to improve nutrition in infants with CF to slow deterioration of pulmonary function and improve survival. A more accurate determination of body composition in infants with cystic fibrosis may allow targeting of children at highest risk of nutritional compromise and suggest improved nutritional interventions.