Ece D. Gamsiz

Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.

Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. Model development.

The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo‐equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design. Biotechnol. Bioeng. 2010; 105: 409–420.

Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein

Activity-dependent neuroprotective protein (ADNP) is a highly conserved transcription factor comprised of nine-zinc finger domains and a homeobox domain.1 ,2 It is highly expressed prenatally during critical stages of embryonic brain development.3 Knockout (KO) mouse embryos demonstrate severe neurodevelopmental morphological profiles.4 Although the ADNP KO is lethal, heterozygous embryos demonstrate typical embryogenesis yet display a neurodevelopmental delay phenotype including decreased neuronal survival.3 ,5 Exome sequencing in the Simons Simplex Collection autism dataset identified ADNP mutations as a putative autism gene candidate.6 ,7 Helsmoortel et al 8 recently reported 10 individuals with autism spectrum disorder (ASD) and mutations in exon 5 of the ADNP gene, nine of which were confirmed de novo. These patients also exhibited intellectual disability (ID) and dysmorphic features such as a prominent forehead. Mutations in the ADNP gene are estimated to be present in at least 0.17% of ASD cases. The current report further expands the ADNP phenotype to include abnormalities in the developing visual system (such as eye movement abnormalities and cortical visual impairment). We advise appropriate screening of eye movement and visual symptoms by clinicians in patients who have mutations in ADNP . The 6-year-old patient was the first child born to healthy non-consanguineous parents. Pregnancy was notable for placenta previa and early dilation and effacement of the cervix 3 weeks prior to delivery. The patient was born at 40 weeks via C-section secondary to failure to progress and maternal (i.e. maternal hypertension) hypertension weighing 6 pounds 14 ounces. She had a short stay in the neonatal intensive care unit (NICU) for breathe holding and feeding problems. She was also hospitalised at 6 weeks for an acute life-threatening event of multiple cyanotic episodes thought to be due to breath holding. Our patient has been diagnosed with hypotonia and mixed developmental …

Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation

A model was developed for predicting the influence of cyclodextrins (CDs) delivered as a physical mixture with drug on oral absorption. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. The purpose of this work is to compare the simulation predictions with in vitro as well as in vivo experimental results to test the models ability to capture the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution and absorption kinetics of low solubility drugs (Naproxen and Nifedipine) were tested in the presence and absence of CD in a simulated gastrointestinal environment. Model predictions were also compared with in vivo experimental results (Glibenclamide and Carbamazepine) from the literature to demonstrate the models ability to predict oral bioavailability. Comparisons of simulation and experimental results indicate that a model incorporating the influence of CD (delivered as a physical mixture) on dissolution kinetics and binding of neutral drug can predict trends in the influence of CD on bioavailability. Overall, a minimal effect of CD dosed as a physical mixture was observed and predicted. Modeling may aid in enabling rational design of CD containing formulations. Biotechnol. Bioeng. 2010; 105: 421–430.

Drug Salts and Solubilization: Modeling the Influence of Cyclodextrins on Oral Absorption

Substantial effort and resources are spent for the oral delivery of low solubility compounds using drug delivery technologies. Complexation using cyclodextrins (CDs) is one popular strategy used to enhance drug dissolution kinetics and solubility. In addition to delivery technologies, another common method of improving dissolution kinetics of a low solubility compound is to dose it as a salt. It is not often possible to anticipate how effective a technology such as CD will be in a certain formulation in improving drug absorption, leading to a trial-and-error based formulation process; simultaneous use of salt and complexation technologies increases the complexity of the system. A simple dynamic, systems-based model was developed for predicting the influence of CDs on oral absorption of a salt form of low solubility drug administered as a physical mixture with CD, and validated by in vitro experiments. Model predictions indicate that while CD is generally considered a solubilization technology, CD can enhance overall absorption of salt form drug mainly by decreasing the driving force for precipitation through binding free drug in solution. Modeling enabled examination of which physical and chemical properties result in oral absorption enhancement or decrement for drug salt administered as a physical mixture with CD.

Predicting the Effect of Fed-State Intestinal Contents on Drug Dissolution

ABSTRACTPurposeThere are several endogenous and exogenous species in the gastrointestinal (GI) tract which can act as solubilizing agents and thereby affect drug dissolution. The purpose of this study is to understand food effects on drug dissolution and provide insight into their anticipated overall effect on absorption and bioavailability.MethodsDissolution kinetics of 15 drugs of variable logP, charge, and molecular weight were tested in simulated intestinal environment. The ability of a film-equilibrium-based model to predict the influence of a simulated intestinal environment on drug dissolution was examined.ResultsThe most significant improvement in dissolution kinetics and solubility (up to 6-fold) was evident with highly hydrophobic compounds (logP > 4). Improvement in solubility did not always constitute improvement in dissolution kinetics on a relevant time scale. Comparison of simulation and experimental results indicates that a model considering micelle partitioning as a pseudo-equilibrium process can predict trends in the influence of food-related solubilizing agents on drug dissolution kinetics.ConclusionsThe significance of food-related solubilizing agents to drug dissolution is not always obvious, as it depends on multiple physicochemical parameters; however, simple modeling may provide insight into food effects on dissolution and, ultimately, overall absorption and bioavailability of compounds considered for oral formulation.

Genetic Variation in the Oxytocin Receptor Gene is Associated With a Social Phenotype in Autism Spectrum Disorders

Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype–phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485–1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3′ untranslated region (3′‐UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3′UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis.

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

Model Predicting Impact of Complexation With Cyclodextrins on Oral Absorption

Significant effort and resource expenditure is dedicated to enabling low‐solubility oral drug delivery using solubilization technologies. Cyclodextrins (CD) are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. It is not clear prior to developing a drug delivery device with CD what level of absorption enhancement might be achieved; modeling can provide useful guidance in formulation and minimize resource intensive iterative formulation development. A model was developed to enable quantitative, dynamic prediction of the influence of CD on oral absorption of low solubility drug administered as a pre‐formed complex. The predominant effects of CD considered were enhancement of dissolution and slowing of precipitation kinetics, as well as binding of free drug in solution. Simulation results with different parameter values reflective of typical drug and CD properties indicate a potential positive (up to five times increase in drug absorption), negative (up to 50% decrease in absorption) or lack of effect of CD. Comparison of model predictions with in vitro and in vivo experimental results indicate that a systems‐based dynamic model incorporating CD complexation and key process kinetics may enable quantitative prediction of impact of CD delivered as a pre‐formed complex on drug bioavailability. Biotechnol. Bioeng. 2013; 110:2536–2547.