4M study-maternal metabolism, breast milk composition, and infant outcomes
Ellen Demerath, PhD (School of Public Health)
Katherine Jacobs, DO (Department of Obstetrics, Gynecology, and Women's Health), Cheryl Gale, MD (Department of Pediatrics), Dan Knights, PhD (Department of Computer Science and Biotechnology Institute), Samantha Hoffman, MD (Department of Obstetrics, Gynecology, and Women's Health), Stephanie Mackenthun, MD (Department of Obstetrics, Gynecology, and Women's Health)
The 4M cohort adds mothers with gestational diabetes to expand upon the MILK Study cohort, considering the entire range of potential maternal factors impinging on breast milk composition in obese as compared to normal weight women. With the addition of the 4M cohort, we will learn how breastmilk composition differs among women with and without gestational diabetes and how hormones and microbiome affect infant body composition and infant microbiome.
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.
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
Julie Eisengart, PhD, LP (Department of Pediatrics)
Chester B. Whitley PhD, MD (Department of Pediatrics), Amy Esler, PhD (Department of Pediatrics)
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.
Autism spectrum disorders and the gut microbiome
Suma Jacob, MD, PhD (Department of Psychiatry)
Jed Elison, PhD (Institute of Child Development), Amy Esler, PhD (Department of Pediatrics), Brittany Howell, PhD (Institute of Child Development)
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.
Longitudinal assessment of asymptomatic congenital CMV infection in Minnesota infants identified by universal screening: what is risk of sequelae?
Mark Schleiss, MD (Department of Pediatrics)
Jed Elison, PhD (Institute of Child Development), Igor Nestrasil, MD, PhD (Department of Pediatrics), Erin Osterholm, MD (Department of Pediatrics)
Symptomatic congenital CMV (cCMV) infections are commonly encountered in clinical practice, affecting approximately 0.65% of all newborns. Such infections - in symptomatic newborns - carry a substantial risk for long-term neurodevelopmental sequelae including developmental delay, mental retardation, seizure disorders, cerebral palsy, and sensorineural hearing loss. Nucleoside antiviral therapy is associated with only modest improvements in audiological and neurodevelopmental outcomes. It is much less clear how to manage infants identified with asymptomatic cCMV infection. These infants have in the past essentially escaped clinical recognition, precisely because these children are asymptomatic at birth, and there is no universal newborn cCMV screen. However, the landscape of cCMV screening is rapidly evolving, and there is increasing interest in implementation of universal cCMV screening programs. In spite of recent progress, universal newborn screening for congenital CMV in many ways remains an area of scientific uncertainty. The optimal screening methodology remains uncertain. We don’t know if asymptomatic infants should undergo full laboratory and neuroimaging evaluations, or whether treatment of infants with asymptomatic congenital CMV with antivirals should be considered. Our proposal will conduct neurocognitive and neuroimaging studies in asymptomatic infants identified with congenital CMV infection in the context of a universal screening program to address these important areas of knowledge deficit.
SPARK: Simons Foundation powering autism research for knowledge, a national cohort of individuals and families affected by autism spectrum disorder protocol
Suma Jacob, MD, PhD (Department of Psychiatry)
Amy Esler, PhD (Department of Pediatrics)
The purpose of SPARK : Simons Foundation Powering Autism Research for Knowledge (hereinafter referred to as SPARK) is to recruit, engage, and retain a community of 50,000 individuals with ASD along with their family members in the United States to identify the causes of ASD, accelerate clinical research by providing the autism research community with a genotyped cohort of consented participants, and establish a research cohort of individuals and families with ASD. The data generated will facilitate identification of additional genes that contribute strongly to ASD and define their corresponding genotype-phenotype relationships. Data from this cohort will also help identify additional non-genetic causes of ASD. A long term goal of SPARK is to enable genotype-driven clinical research in ASD, which may translate into genotype-driven therapeutics and treatment of ASD. This type of ‘precision medicine’ approach is an emerging strategy for disease treatment and prevention that takes into account individual genetic variability, environment, and lifestyle. Noteworthy advances in precision medicine have been made for specific cancers, but the methodology is not currently available for most diseases. Many researchers are working towards precision medicine, and SPARK is one such project. A limited data set from this study will be made available to qualified researchers, so that scientific and treatment advances can be made as rapidly as possible.