Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ∼1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA

Parenteral CoQ10 Formulation (BPM31510) Significantly Improves Survival In Animal Model Of Leukemia Including The Resolution Of Paraplegia Due To Brain Metastasis

Abstract Leukemia cells exhibit alterations in intermediary metabolism similar to other cancers, wherein ATP sourcing is shunted from mitochondrial oxphos towards glycolytic preponderance (Warburg Effect) to meet oncogenic proliferative demands. A consequence of this metabolic switch is the simultaneous short-circuit of the programmed death pathways, leading to a immortalization program in cancer cells including leukemia. Delivery of high levels of CoQ10 in a lipid nanodispersion mixture (BPM31510) has been demonstrated to preferentially shift metabolic networks from glycolysis towards mitochondrial-centric oxphos and recapitulation of apoptotic pathways in various cancers in vitro and in vivo models. Given the centrality of the Bcl-2 involvement in the etiology of leukemia, this study focused on investigation of the effectiveness of BPM31510 in animal models of erythroid and myeloid leukemia. Human acute erythro-leukemia (K562) and acute myeloid leukemia (KG1) models were developed in immune-compromised mice. The mice (total n=120 for each model respectively) were randomized into four (n=30/group) treatment groups: Untreated (control); BPM31510 (75 mg/kg, once/day); chemotherapy (Adriamycin [5mg/kg; once/wk]+AraC [25mg/kg; 5 days] and BPM31510+chemotherapy. All dosing were intravenous and followed a protocol of 3wk treatment followed by 1wk rest. In both leukemia models, combination of BPM31510 with chemotherapy was associated with significant increase in survival compared to other groups. BPM31510 alone improved survival compared to chemotherapy in myeloid leukemia, not in erythroleukemia model. In a separate study, a rat (Fisher 344) chloroleukemia (MIA C51) model of CNS leukemia was developed that demonstrated paraplegia and urinary retention as a result of brain metastasis. Administration of BPM31510 (50 mg/kg/day, IP) was associated with complete resolution of limb paralysis demonstrating the ability of BPM31510 in penetrating into the CNS. Moreover, BPM31510 (50 mg/kg/day, IP) administration was associated with significant increase in survival in animals with metastasis to the lungs and liver. The data provides encouraging evidence of the potential translational use of CoQ10 containing BPM31510 in the treatment of leukemia. A Phase 1 study in relapse acute leukemia is to be started shortly. Disclosures: Narain: Berg: Employment. Akmaev:Berg: Employment. Benaim:Berg: Employment. Sarangarajan:Berg: Employment. Jimenez:Berg: Membership on an entity’s Board of Directors or advisory committees

Abstract 5230: Berg Interrogative Biology™ Informatics Suite: data driven integration of multi-omic technologies using Bayesian AI

Abstract The Berg Interrogative Biology™ Informatics Suite is an automated data-processing instrument for generation of actionable hypotheses using data generated exclusively via the Berg Interrogative Biology™ approach. The Berg Interrogative Biology™ is a platform that systematically interrogates the biological environment in proprietary in-vitro and in-vivo biological model systems. The biologically relevant data output include molecular data from multi-omics technologies such as proteomics, lipidomics, metabolomics and genomics generated within the context of Berg Interrogative Biology™ is subsequently processed by a set of mathematical algorithms within Informatics Suite. The steps include filtering of datasets with methods that allows for missing data without compromising data quality, normalization of data using technology specific methods, imputation of missing data by rigorous statistical approaches, and generation of a molecular interactome model by integrating data across experiments and technologies. Consequently, the multi-omics data is subjected to analysis using a Bayesian Network inference approach and a multi-omic cause-and-effect relationships are inferred for each analyzed condition de novo. In addition to inferring cross-molecular species interaction networks, in-silico perturbation experiments may be performed to predict cascades of molecular and phenotypic responses to a gene or protein knock-down or over-expression model. Model response is analyzed by statistical techniques and submitted to a Rich Internet Application (RIA) that allows a dynamic and interactive meta-analysis of integrated molecular interaction networks. The Informatics Suite pipeline was applied to multi-omic data set generated via the use of the Berg Interrogative Biology™ process in an in-vitro model of angiogenesis. Comprehensive implementation of the platform technology with the informatics workflow not only identified new and physiologically relevant molecular interactions, but also confirmed previously known canonical interaction pathways described in the literature. Thus, the Informatics Suite within the Berg Interrogative Biology™ platform represents a novel computational component for integrative analysis of multi-omics molecular data that is fast, accurate and leads to a rank-ordered number of actionable hypotheses positioning Berg Interrogative Biology™ as one of the most innovative and efficient approaches in drug and biomarker discovery. Citation Format: Leonardo Rodrigues, Vijetha Vemulapalli, Anthony Walshe, Min Du, Michael Keibish, Joaquin J. Jimenez, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Viatcheslav R. Akmaev, Niven R. Narain. Berg Interrogative Biology™ Informatics Suite: data driven integration of multi-omic technologies using Bayesian AI. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5230. doi:10.1158/1538-7445.AM2013-5230</jats:p

A next generation sequencing based approach to identify extracellular vesicle mediated mRNA transfers between cells

Abstract Background Exosomes and other extracellular vesicles (EVs) have emerged as an important mechanism of cell-to-cell communication. However, previous studies either did not fully resolve what genetic materials were shuttled by exosomes or only focused on a specific set of miRNAs and mRNAs. A more systematic method is required to identify the genetic materials that are potentially transferred during cell-to-cell communication through EVs in an unbiased manner. Results In this work, we present a novel next generation of sequencing (NGS) based approach to identify EV mediated mRNA exchanges between co-cultured adipocyte and macrophage cells. We performed molecular and genomic profiling and jointly considered data from RNA sequencing (RNA-seq) and genotyping to track the “sequence varying mRNAs” transferred between cells. We identified 8 mRNAs being transferred from macrophages to adipocytes and 21 mRNAs being transferred in the opposite direction. These mRNAs represented biological functions including extracellular matrix, cell adhesion, glycoprotein, and signal peptides. Conclusions Our study sheds new light on EV mediated RNA communications between adipocyte and macrophage cells, which may play a significant role in developing insulin resistance in diabetic patients. This work establishes a new method that is applicable to examining genetic material exchanges in many cellular systems and has the potential to be extended to in vivo studies as well