Restoring sight with native cell reprogramming

Stower, Hannah

doi:10.1038/s41591-018-0192-6

Cited by 4 publications

(4 citation statements)

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“…Müller glia are a critical therapeutic target for retinal degeneration. With the recent success of reprogramming Müller glia into functional rod photoreceptors, Müller glia remain key targets for regenerating the retina [ 34 , 35 ]. Although the ONH sits at the back of the eye, the ILM is not part of the ONH composition and it becomes thinner as the retinal interface gets closer to the ONH, which decreases the difficulty of transducing the ONH.…”

Section: Discussionmentioning

confidence: 99%

The effects of PEGylation on LNP based mRNA delivery to the eye

et al. 2020

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Gene therapy is now an effective approach to treat many forms of retinal degeneration. Delivery agents that are cell-specific, allow for multiple dosing regimens, and have low immunogenicity are needed to expand the utility of gene therapy for the retina. We generated eight novel lipid nanoparticles (LNPs) ranging in size from 50 nm to 150 nm by changing the PEG content from 5% to 0.5%, respectively. Subretinal injections of LNP-mRNA encoding luciferase revealed that 0.5% PEG content within nanoparticles elicits the highest expression. Similar injections of LNP delivered cre mRNA into Ai9 mice revealed cell-specific protein expression in the retinal pigment epithelium (RPE), confirmed by fundus photography and immunohistochemistry of whole globe cross-sections. To investigate mechanisms of LNP delivery to the eye, we injected mCherry mRNA using the subretinal approach in apoE -/- and Mertk -/- mice. RPE transfection was observed in both mouse models suggesting that LNP intracellular delivery is not solely dependent on apolipoprotein adsorption or phagocytosis. To investigate LNP penetration, particles were delivered to the vitreous chamber via an intravitreal injection. The 0.5% PEG particles mediated the highest luciferase activity and expression was observed in the Müller glia, the optic nerve head and the trabecular meshwork, but failed to reach the RPE. Overall, particles containing less PEG (~150 nm in size) mediated the highest expression in the eye. Thus far, these particles successfully transfect RPE, Müller cells, the optic nerve head and the trabecular meshwork based on route of administration which can expand the utility of LNP-mediated gene therapies for the eye.

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Section: Discussionmentioning

confidence: 99%

The effects of PEGylation on LNP based mRNA delivery to the eye

et al. 2020

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“…A more robust polygenic score was able to identify 8% of population at a greater than threefold increased risk of CAD (98). Given the ongoing identification of novel genetic variants associated with CAD and the continuously decreasing costs of genotyping arrays, implementation of such GRS into everyday clinical practice starts to be considered as a cost-effective method for improving the effectiveness of prevention and treatment for CAD (99,100).…”

Section: Genetic Risk Scoresmentioning

confidence: 99%

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches

Kuś

Chaker

Teumer

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels. Evidence Acquisition This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease. Evidence Synthesis Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint. Conclusions Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.

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“…It is important to recognize that the effects of this lack of diversity extend beyond discovery science to translational studies because the resulting gaps in knowledge may lead to missed opportunities for developing clinical guidelines, better tailoring of clinical guidelines and treatment protocols and developing new therapeutic agents 45,54 . Highlighting these issues further is the recent call for better calibration of polygenetic risk scores (PRS) to enhance transethnic utility with the hope of not exacerbating already unacceptable health disparities as PRS is used to identify high-risk individuals for early intervention in clinical and public health settings 55,56 .…”

Section: Discussionmentioning

confidence: 99%

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

et al. 2019

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Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10 −9 ). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.

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Restoring sight with native cell reprogramming

Cited by 4 publications

References 0 publications

The effects of PEGylation on LNP based mRNA delivery to the eye

The effects of PEGylation on LNP based mRNA delivery to the eye

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

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