Genetic/Congenital/Developmental Condition

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)

Principal Investigator:

Chester B. Whitley PhD, MD (Department of Pediatrics)

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Collaborators:

Julie Eisengart, PhD (Department of Pediatrics), Bradley S. Miller PhD, MD (Department of Pediatrics)

Abstract:

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)

Principal Investigator:

Suma Jacob, MD, PhD (Department of Psychiatry)

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Collaborators:

Bradley Miller, MD, PhD (Department of Pediatrics), Rebekah Hudock, PhD (Department of Pediatrics)

Abstract:

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 III, randomized, double-blind, placebo-controlled, efficacy and safety study of balovaptan in adults with autism spectrum disorder with a 2-year open-label extension

Principal Investigator:

Suma Jacob, MD, PhD (Department of Psychiatry)

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Collaborators:
Abstract:

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 sum, 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. A V1a antagonist may provide a novel and first approach to treat the core social and communication deficits in ASD.

An open-label, single-arm, multicenter study of intracerebral administration of adeno-associated viral vectors serotype rh10 carrying the human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA for the treatment of mucopolysaccharidosis type IIIA

Principal Investigator:

Julie Eisengart, PhD, LP (Department of Pediatrics)

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Collaborators:

Chester B. Whitley PhD, MD (Department of Pediatrics), Amy Esler, PhD (Department of Pediatrics)

Abstract:

Mucopolysaccharidosis IIIA (MPS IIIA), also known as Sanfilippo Syndrome Type A, is a rare pediatric disease that is a uniformly fatal childhood disease. This autosomal recessive lysosomal storage disease is caused by a missing or dysfunctional catabolic protein, leading to the subsequent accumulation of substrates in the cell, resulting in very severe cellular and organ dysfunctions, particularly prominent in the central nervous system. Severe behavior dysregulation, sleep disturbance, and cognitive decline are the phenotypic hallmarks of MPS IIIA.

MPS IIIA has an incidence of 0.44-1.16 per 100,000 births and is caused by autosomal recessive genetic defects of the N-sulfoglucosamine sulfohydrolase (SGSH) gene localized to 17q25.3. SGSH is a secreted enzyme involved in the stepwise degradation of heparan sulfate (HS). A  deficiency in SGSH leads to an accumulation of HS in cells and affects cellular functioning  including lysosomal clearance. Currently, there ae no disease-modifying treatment(s) available or MPS IIIA.

The treatment proposed here, using Lysogene's in-vivo gene therapy LYS-SAF302 product (adeno-associated viral vector serotype rh.10 canying the human N-sulfoglucosamine sulfohydrolase cDNA)  consists of an intracerebral multi-injection site administration performed in a single operation.  It is hoped that treated patients would maintain existing cognitive and neurodevelopmental capabilities and possibly would acquire new skills.

Assessment of body composition in infants with cystic fibrosis

Principal Investigator:

Elissa M. Downs, MD, MPH (Pediatric Gastroenterology, Hepatology, and Nutrition)

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Collaborators:

Sarah Jane Schwarzenberg, MD (Pediatric Gastroenterology, Hepatology, and Nutrition), Terri Laguna, MD (Pediatric Pulmonary Medicine), Sara Ramel, MD (Department of Neonatology)

Abstract:

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. 

Autism spectrum disorders and the gut microbiome

Principal Investigator:

Suma Jacob, MD, PhD (Department of Psychiatry)

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Collaborators:

Jed Elison, PhD (Institute of Child Development), Amy Esler, PhD (Department of Pediatrics), Brittany Howell, PhD (Institute of Child Development)

Abstract:

Standard practice has not been established for the evaluation of possible GI morbidity when an individual with ASD presents with behavioral problems of new onset. In addition, it is hypothesized that gut-based processes may have a more direct pathophysiologic role in ASD due to 1) gut-based inflammatory processes that result in neuroinflammation and consequent alterations in brain function, 2) changes to the gut microbiota and the associated metabolome result in altered neurobehavioral function, or 3) dietary and nutritional mechanisms alter the relationship between GI and CNS function. This study aims to identify differences in gut microbiome composition between healthy controls, individuals with ASD diagnosis and those without, and to confirm that rigid-compulsive behaviors (RCB) in ASD are associated with GI symptoms and to examine if those with higher levels of these ASD behaviors have a distinct microbiome profiles.

Choline supplementation as a neurodevelopmental intervention in fetal alcohol spectrum disorders

Principal Investigator:

Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)

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Collaborators:

Michael K. Georgieff, M.D. (Department of Pediatrics), Stephanie Carlson, Ph.D. (Institute of Child Development)

Abstract:

Recent data indicate that 2-5% of the U.S. population has Fetal Alcohol Spectrum Disorder (FASD) – a set of physical anomalies and neurodevelopmental deficits caused by prenatal alcohol exposure (May, Fiorentino et al. 2011). Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population and no clinical trials that have attempted to directly address the neurodevelopmental deficits that are so debilitating for these individuals. There is, however, a promising line of translational research that suggests a potential role for micronutrient interventions. At the top of the list is choline, an essential nutrient for humans that is critical for normal brain development during gestation and early childhood. Although the human body produces choline, the demand cannot be met entirely endogenously and thus, some choline must be consumed in food. Extensive pre-clinical work has provided evidence that choline supplementation is effective in attenuating the neurodevelopmental deficits caused by prenatal alcohol exposure in animal models (Thomas, Biane et al. 2007, Ryan, Williams et al. 2008). Our group has taken the initial steps toward translating this work to humans. We first conducted a two-year pilot study to ensure the feasibility, tolerability, and safety of choline supplementation in 20 children with FASD (Wozniak, Fuglestad et al. 2013). Next, we completed a three-year pilot study of 40 additional children with the goals of establishing a target dosage for young children and testing efficacy in the domain of memory (Wozniak, Fuglestad et al. under review). Together, data from these two studies demonstrate that choline supplementation in 2-3 year old children with FASD improves explicit memory – a core function that is essential for normal cognitive development. Based on the time periods in which choline is effective in pre-clinical models of FASD and on the fact that the first years of human life represent a period of intense brain development, choline supplementation in young children appears to have significant potential as an intervention for neurodevelopmental disorders including FASD.

Effects of single-session transcranial direct current stimulation in children with cerebral palsy

Principal Investigator:

Bernadette Gillick, PhD, MSPT, PT (Department of Rehabilitative Medicine)

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Abstract:

Neurorehabilitation in cases of hemiparesis has primarily focused on intensive motor training to encourage use of the affected extremities in an effort to produce use-dependent neuroplasticity in the brain. Such interventions are effective, but require a burdensome amount of time, 60-90 hours per week, for both the child and therapist. Furthermore, some children do not respond at all to such training.

Neuromodulation is a relatively new field that aims to influence the brain’s neuronal activity through direct application of magnetic (TMS) or electric (tDCS) energy. It is thought the combination of neuromodulation and motor training may reduce the dosage of training needed, and would promote recovery to a greater extent for more individuals. Indeed, previous work in adult stroke demonstrate a benefit of combining repetitive TMS (rTMS) and tDCS with motor training, compared to training alone. These types of synergistic interventions are just beginning to be used in children with UCP, with some preliminary data showing potential benefit.

This study aims to offer insight into the mechanisms of tDCS and lead the field toward a better understanding of how tDCS be implemented in a neurorehabilitation setting for both children and potentially adults.

Event-related potentials for early detection of the cerebral form of X-linked adrenoleukodystrophy: a feasibility study

Principal Investigator:

Rene Pierpont, Ph.D., L.P. (Department of Pediatrics)

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Collaborators:

Julie Eisengart, Ph.D. (Department of Pediatrics), Weston Miller, MD (Department of Pediatrics), Paul Orchard, MD (Department of Pediatrics), Michael Georgieff, MD (Department of Pediatrics)

Abstract:

Adrenoleukodystrophy (ALD) is a devastating childhood neurodegenerative disease for which the onset of central nervous system (CNS) involvement is unpredictable, although previous research has shown that thirty-five percent of affected boys develop clinically evident cerebral involvement (cALD) between 4-10 years of age (1). The disease is characterized by progressive cerebral demyelination and inflammation. Devastating neurological and cognitive decline is associated with cALD, with death occurring a few years following the onset of clinically-evident disease.  Patients with cALD have a fairly predictable, consistent pattern of white matter disease progression.  Previous studies in other at-risk populations have demonstrated the ability of scalp-recorded event-related potentials (ERPs) to detect brain functional abnormalities prior to the onset of behavioral symptomatology. Early detection of the cerebral form of ALD would revolutionize treatment outcomes for patients with this condition. Given the fairly consistent pattern of cerebral disease progression within white matter tracts, and the fact that latency of ERP components are sensitive to changes in myelination and synaptic efficiency, we hypothesize that ERPs may enable more reliable prediction of disease onset than traditional behavioral measures, for which performance may be vulnerable to non-disease influences such as fatigue or anxiety.

Long-term follow-up of term survivors of hypoxic-ischemic encephalopathy: an evaluation of brain function and structure

Principal Investigator:

Katie Pfister, MD (Pediatrics, Division of Neonatology)

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Collaborators:

Elizabeth Zorn, MD (Pediatrics: Division of Neonatology), Christopher Boys, PhD, LP (Department of Pediatrics), Katie Thomas, PhD (Institute of Child Development)

Abstract:

A prospective observational cohort study design will be used to determine whether survivors of HIE who were treated with therapeutic hypothermia have deficits in memory or executive function at age 4-5 years, and whether there are observable changes in brain structure or connectivity. MRI with diffusion tensor imaging will be used to assess brain volumes, structure, and white matter connectivity. Behavioral assessments (WPPSI-IV and NEPSY-II) and parental questionnaires (BRIEF-P) will be used to assess overall intellectual function, executive function, and memory.

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