Biomarkers in Pharmaceutical Research

Zhao, Xuemei; Modur, Vijay; Carayannopoulos, Leonidas N.; Laterza, Omar

doi:10.1373/clinchem.2014.231712

Cited by 48 publications

(24 citation statements)

References 66 publications

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“…57 NEFL assays in CMT has provided an important marker of axonal degeneration in CMT1A, 9 but there is currently a lack of biomarkers to assess disease processes in the SCs that are most directly affected by the PMP22 gene duplication. Biomarkers can be used to not only measure disease process (NEFL levels) and disease burden (MRI), but also target engagement for a given therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers can be used to not only measure disease process (NEFL levels) and disease burden (MRI), but also target engagement for a given therapy. 57 NEFL assays in CMT has provided an important marker of axonal degeneration in CMT1A, 9 but there is currently a lack of biomarkers to assess disease processes in the SCs that are most directly affected by the PMP22 gene duplication. Several candidate therapies reduce PMP22 levels in CMT1A rodent models and thereby ameliorate the symptoms of PMP22 overexpression.…”

Section: Discussionmentioning

confidence: 99%

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Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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Objective: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SCs) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls. Methods: We have developed methods to normalize PMP22 transcript levels to SC-specific genes that are not altered by CMT1A status. Several CMT1A-associated genes were assembled into a custom Nanostring panel to enable precise transcript measurements that can be normalized to variable SC content. Results: The digital expression data from Nanostring analysis showed reproducible elevation of PMP22 levels in CMT1A versus control skin biopsies, particularly after normalization to SC-specific genes. Interpretation: This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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“…For example, a stratification biomarker for ASD might indicate a portion of children on the spectrum likely to respond to a specific treatment. Target engagement biomarkers provide evidence that an intervention is influencing an intended process (12). In ASD, a target engagement biomarker might reflect that a specific medication is altering neural activity in a brain region of interest.…”

Section: Biomarker Definition and Subtypesmentioning

confidence: 99%

Considerations in biomarker development for neurodevelopmental disorders

McPartland¹

2016

Current Opinion in Neurology

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Purpose of review Despite significant progress in recognizing the biological bases of autism spectrum disorder, diagnosis and treatment rely primarily on subjective evaluation of behavior. This review highlights the challenges unique to neurodevelopmental disorders that have limited biomarker development. Recent findings The field of neurodevelopmental disorders requires objective quantification of biological processes to enable designation of subgroups likely to benefit from specific treatments, index diagnostic status/risk, demonstrate engagement of targeted systems, and provide more rapid assessment of change than traditional clinical observation and caregiver report measures. Summary Useful biomarkers for neurodevelopmental disorders must be reliable across development, evident at the individual level, and specific to a unit of analysis, be it diagnostic status or functional process. The ultimate value of biomarkers for neurodevelopmental disorders will relate to their ease of use, cost, scalability, sensitivity, and methodological objectivity.

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“…In this context, a major challenge ahead is the identification of bona fide target engagement biomarkers [70, 71] to identify in short-term and in readily-accessible tissues, the status of blockade of the RAGE pathway. It is plausible that measures of the various classes of RAGE ligands may be specific to different stages of the disease process.…”

Section: 0 Five- Year Viewmentioning

confidence: 99%

Glycation & the RAGE axis: targeting signal transduction through DIAPH1

Shekhtman

Ramasamy

Schmidt

2016

Expert Review of Proteomics

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Introduction The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

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Biomarkers in Pharmaceutical Research

Cited by 48 publications

References 66 publications

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Considerations in biomarker development for neurodevelopmental disorders

Glycation & the RAGE axis: targeting signal transduction through DIAPH1

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