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Pharmacogenetics for type 2 diabetes: practical considerations for study design.

ABSTRACT: There is a relative dearth of studies designed to elucidate genetic variation that can explain differences in the response to diabetes pharmacotherapy. When designing such studies, appropriate consideration of the various nongenetic variables that can affect the treatment response is necessary. In addition, disease stage and prior pharmacotherapy also influence drug efficacy. Selecting the appropriate genetic variant to test in such studies is also important, and common variants (known to be functional or otherwise) in a given candidate locus should be tested for the effect on the treatment response. Finally, an appropriate measure of treatment response is necessary to enable detection of pharmacogenetic effects. Perhaps prior to undertaking such studies, smaller studies utilizing well-characterized, homogenous populations with normal glucose tolerance or prediabetes (to avoid the problem of disease effects on treatment response) and surrogate measures of response such as insulin secretion should be completed.

SUBMITTER: Vella A

PROVIDER: S-EPMC2769969 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Pharmacogenetics for type 2 diabetes: practical considerations for study design.

Vella Adrian A

Journal of diabetes science and technology 20090701 4

There is a relative dearth of studies designed to elucidate genetic variation that can explain differences in the response to diabetes pharmacotherapy. When designing such studies, appropriate consideration of the various nongenetic variables that can affect the treatment response is necessary. In addition, disease stage and prior pharmacotherapy also influence drug efficacy. Selecting the appropriate genetic variant to test in such studies is also important, and common variants (known to be fun ...[more]

PMID: 20144317

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Project description:Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. HACA-PD1 was adopted as the naming convention for aglycosylated tracer variants. NOD scid γ-(NSG) mice were inoculated with subcutaneous tumors engineered to either be constitutively positive (CT26 hPD-L1) or be negative (ΔmPD-L1 CT26) for human PD-L1 expression. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.75-2.25 MBq (∼10 μg) of an engineered radiotracer variant and imaged. At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance. In imaging studies, aglycosylated 64Cu-NOTA-HACA-PD1 most accurately visualized human PD-L1 expression in vivo. We reasoned that because of the scaffold's small size (14 kDa), its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal 68Ga. At 1 h after injection, 68Ga-NOTA-HACA-PD1 and 68Ga-DOTA-HACA-PD1 exhibited promising target-to-background ratios in ex vivo biodistribution studies (12.3 and 15.2 tumor-to-muscle ratios, respectively). Notably, all HAC-PD1 radiotracer variants enabled much earlier detection of human PD-L1 expression (1 h after injection) than previously reported radiolabeled antibodies (>24 h after injection). This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints.

Dataset Information

Pharmacogenetics for type 2 diabetes: practical considerations for study design.

Publications

Pharmacogenetics for type 2 diabetes: practical considerations for study design.

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