EU pathway for improve rare disease identification and treatment

New EU platform to support better rare disease diagnosis and treatment

The European Commission is launching a new online knowledge-sharing platform to support better diagnosis and treatment for more than 30 million Europeans living with a rare disease.

Currently a vast amount of data on patients with specific conditions is scattered across Europe in about 600 'registries' – databases that hold information on patients with specific conditions. Data is not collected EU-wide and there are no shared standards to analyse the information that is available on rare diseases. The new European Platform on Rare Diseases Registration will bring this data together supporting the quality research that can enhance diagnosis and treatment outcomes - helping to improve the lives of patients and their families.

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Big players dominate global Liver Cancer diagnostics for foreseeable future

The Global Liver Cancer Diagnostic Market to 2025 - Leading Players are Illumina, Qiagen, F. Hoffmann-La Roche, Siemens Healthcare, and Thermo Fisher Scientific

Dublin, March 08, 2019 (GLOBE NEWSWIRE) -- The "Liver Cancer Diagnostic Market Size, Share & Trends Analysis Report By Screening Type (Biopsy, Endoscopy, Laboratory Tests, Imaging), By Region (North America, APAC, Europe), And Segment Forecasts, 2019 - 2025"report has been added to ResearchAndMarkets.com's offering.

The global liver cancer diagnostics market size is expected to reach USD 15.4 billion by 2025. The market is projected to expand at a CAGR of 8.1% over the estimated time period.

Rise in disease incidence coupled with growing demand for novel diagnosis products are thrusting the growth of the market. Hepatocellular Carcinoma (HCC) is the most common type of primary liver cancer in adults. It is among the common causes of death in people with liver cirrhosis and the third-leading cause of cancer deaths across the globe. Poor survival rate and lack of therapies has made this disease a crucial health issue worldwide.

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Single-cell sequencing reveals important cancer mutation signatures (original article)

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

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Mutation bursts associated with cancer -- a very good summary

Researchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage—mutational fingerprints that represent the origins of cancer—were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious.

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Original article here …

Potential to remove HIV from infected cells

‘Molecular scissors’ successfully remove HIV genes from all tissues in infected monkeys

The top story from the Conference on Retroviruses and Opportunistic Infections (CROI 2019) in Seattle this week has been a likely second HIV cure. However, the cure involved an expensive and risky therapy – a bone-marrow transplant – that would never be broadly applicable.

Just as significant in the long term may be a study reported in the same session that used much more benign technology to achieve what may be a cure in monkeys.

A team of researchers at Temple University in Philadelphia, USA, has removed the retroviral genes from the cells of monkeys infected with SIV, the monkey analogue of HIV. The researchers found that the gene-snipping enzyme they used, contained within the shell of a common cold-type virus so that it could simulate an infection and enter cells, successfully removed the SIV genes from a majority – and possibly all – cells in all the monkeys’ organs where levels were measured, including hard-to-access ones such as the brain.

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Let's now worry about designer babies ...

The Dawn of Intelligent Designer Babies

While selecting or editing embryos in favour of certain attributes may seem like a phenomenon of the distant future, the company Genomic Prediction in the United States has recently announced their advanced technology that would allow parents to screen for several complex traits, most controversially being low intelligence. This process would give the option of excluding embryos during in vitro fertilisation (IVF) that have a high risk of having “mental disability,” defined as an IQ of 25 points below average. While Genomic Prediction explicitly states that this will not be used to select for embryos with the potential for abnormally high intelligence, co-founder Stephen Hsu claims it is entirely feasible and states “I think people are going to demand that. If we don’t do it, some other company will.”

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Insights into how prostate cancers become resistant, and new potential targets (original article)

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

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Human disease models made in frogs with CRISPR

Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system

Abstract

Precise single-base editing in Xenopus tropicalis would greatly expand the utility of this true diploid frog for modeling human genetic diseases caused by point mutations. Here, we report the efficient conversion of C-to-T or G-to-A in X. tropicalis using the rat apolipoprotein B mRNA editing enzyme catalytic subunit 1–XTEN–clustered regularly interspaced short palindromic repeat–associated protein 9 (Cas9) nickase–uracil DNA glycosylase inhibitor–nuclear localization sequence base editor [base editor 3 (BE3)]. Coinjection of guide RNA and the Cas9 mutant complex mRNA into 1-cell stage X. tropicalis embryos caused precise C-to-T or G-to-A substitution in 14 out of 19 tested sites with efficiencies of 5–75%, which allowed for easy establishment of stable lines. Targeting the conserved T-box 5 R237 and Tyr C28 residues in X. tropicalis with the BE3 system mimicked human Holt-Oram syndrome and oculocutaneous albinism type 1A, respectively. Our data indicate that BE3 is an easy and efficient tool for precise base editing in X. tropicalis.—Shi, Z., Xin, H., Tian, D., Lian, J., Wang, J., Liu, G., Ran, R., Shi, S., Zhang, Z., Shi, Y., Deng, Y., Hou, C., Chen, Y. Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system.

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Increasing CRISPR efficiency, and specificity with zinc-finger proteins (original article)

Diversifying the structure of zinc finger nucleases for high-precision genome editing

Abstract—Genome editing for therapeutic applications often requires cleavage within a narrow sequence window. Here, to enable such high-precision targeting with zinc-finger nucleases (ZFNs), we have developed an expanded set of architectures that collectively increase the configurational options available for design by a factor of 64. These new architectures feature the functional attachment of the FokI cleavage domain to the amino terminus of one or both zinc-finger proteins (ZFPs) in the ZFN dimer, as well as the option to skip bases between the target triplets of otherwise adjacent fingers in each zinc-finger array. Using our new architectures, we demonstrate targeting of an arbitrarily chosen 28 bp genomic locus at a density that approaches 1.0 (i.e., efficient ZFNs available for targeting almost every base step). We show that these new architectures may be used for targeting three loci of therapeutic significance with a high degree of precision, efficiency, and specificity.

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New insights into tissue-localized immunity in lung transplants

Generation and persistence of human tissue-resident memory T cells in lung transplantation

Tissue-resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess.  By studying donor and recipient T cells in transplanted lungs, Snyder et al. have provided a rare glimpse into the generation and maintenance of human TRM. Whereas donor T cells were barely detectable in blood within 10 weeks after transplantation, donor TRM were abundant and persisted in transplanted lungs for more than a year. Recipient T cells infiltrating the lung gradually acquired TRM profiles over time as determined by analyses of T cells from bronchoalveolar lavages. In this 20-patient cohort, persistence of donor lung TRM correlated with improved clinical outcome, although further studies are needed to understand their role in graft retention.

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CRISPR-based gene therapy, speculating about a time-table

We’re still a long way from using gene-editing for medical conditions?

Gene editing has been in the news lately due to an ethically reckless experiment in which human embryos were subjected to an inefficient form of gene editing. The subjects, now born, gained uncertain protection from HIV in exchange for a big collection of potential risks. A large number of ethicists and scientists agreed that this isn't the sort of thing we should be using gene editing for.

Gene editing will likely always come with a bit of risk; when you're cutting and pasting DNA in millions of cells, extremely rare events can't be avoided. So the ethical questions come down to how we can minimize those risks and what conditions make them worth taking.

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Centers for Medicare & Medicaid Services cancer sequencing dust-up

CMS Acknowledges Stakeholder Concerns Over Decision Not to Cover Germline NGS in Early Cancer Patients

NEW YORK (GenomeWeb) – The Centers for Medicare & Medicaid Services issued a notice this week acknowledging the confusion over its coverage policy for germline next-generation sequencing for cancer patients.

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Single-molecule quantum sequencing method for detecting Anti-Cancer drug incorporation into DNA

DNA is small. Really, really, small. So, when researchers want to study the structure of a single-stranded DNA, they can’t just pull out their microscopes: they have to get creative.

In a study published this week in Scientific Reports, researchers from Japan’s Osaka University explain how they came up with a really small solution to the challenge of studying anti-cancer drugs incorporated into single strands of DNA.

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Next-next generation tool for improving traditional chemotherapies

Direct Analysis of Incorporation of an Anticancer Drug into DNA at Single-Molecule Resolution

Identifying positions at which anticancer drug molecules incorporate into DNA is essential to define mechanisms underlying their activity, but current methodologies cannot yet achieve this. The thymidine fluorine substitution product trifluridine (FTD) is a DNA-damaging anticancer agent thought to incorporate into thymine positions in DNA. This mechanism, however, has not been directly confirmed. Here, we report a means to detect FTD in a single-stranded oligonucleotide using a method to distinguish single molecules by differences in electrical conductance. Entire sequences of 21-base single-stranded DNAs with and without incorporated drug were determined based on single-molecule conductances of the drug and four deoxynucleosides, the first direct observation of its kind. This methodology may foster rapid development of more effective anticancer drugs.

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Cancer mutation characterization with machine learning (original article -- very cool)

Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models

Loss of DNA repair mechanisms can leave specific mutation signatures in the genomes of cancer cells. To identify cancers with broken DNA-repair processes, accurate methods are needed for detecting mutation signatures and, in particular, their activities or probabilities within individual cancers. In this paper, we introduce a class of statistical modeling methods used for natural language processing, known as “topic models”, that outperform standard methods for signature analysis. We show that topic models that incorporate signature probability correlations across cancers perform best, while jointly analyzing multiple mutation types improves robustness to low mutation counts.

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Smart stats make use of large-scale health insurance claims

Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes

We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h2 = 0.311) and shared environmental variance (c2 = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (varSES = 0.002), daily air quality (varAQI = 0.0004), and average temperature (vartemp = 0.001) overall, as well as for individual phenotypes. We found significant heritability and shared environment for a number of comorbidities (h2 = 0.433, c2 = 0.241) and average monthly cost (h2 = 0.290, c2 = 0.302). All results are available using our Claims Analysis of Twin Correlation and Heritability (CaTCH) web application.

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Autism GWAS finds common risk variants

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci.

Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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Insomnia GWAS with 1.3 million individuals yields results

Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited.

Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints.

We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.

Four new bases available for synthetic biology (original article)

Hachimoji DNA and RNA: A genetic system with eight building blocks

Expanding the genetic code

DNA and RNA are naturally composed of four nucleotide bases that form hydrogen bonds in order to pair. Hoshika et al. added an additional four synthetic nucleotides to produce an eight-letter genetic code and generate so-called hachimoji DNA. Coupled with an engineered T7 RNA polymerase, this expanded DNA alphabet could be transcribed into RNA. Thus, new forms of DNA that add information density to genetic biopolymers can be generated that may be useful for future synthetic biological applications.

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Improved CRISPR efficiency in DMD treatment

Scientists find method to boost CRISPR efficiency

Scientists have developed a method to boost the efficiency of CRISPR gene editing in Duchenne muscular dystrophy (DMD), according to a study that could have implications for optimizing gene therapies for other diseases.

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