Posted on: February 2, 2022 Posted by: Spencer Comments: 0
Given the recent success of gene therapy modalities and the growing number of cell and gene-based therapies in clinical development across many different therapeutic areas, it is evident that this evolving field holds great promise for the unmet medical needs of patients. The recent approvals of Luxturna® and Zolgensma® prove that recombinant adeno-associated virus (rAAV)-based gene therapy is a transformative modality that enables curative treatment for genetic disorders.
Over the last decade, Takeda has accumulated significant experience with rAAV-based gene therapies, especially in the early stage of development. In this review, based on the learnings from Takeda and publicly available information, we aim to provide a guiding perspective on Drug Metabolism and Pharmacokinetics (DMPK) substantial role in advancing therapeutic gene therapy modalities from nonclinical research to clinical development, in particular the characterization of gene therapy product biodistribution, elimination (shedding), immunogenicity assessment, multiple platform bioanalytical assays, and first-in-human (FIH) dose projection strategies. Graphical abstract.

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through Joplink  Actin Capping & Actin-Binding Recombinants

NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice.
In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction.
Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

Pseudotyped Vesicular Stomatitis Virus-Severe Acute Respiratory Syndrome-Coronavirus-2 Spike for the Study of Variants, Vaccines, and Therapeutics Against Coronavirus Disease 2019

World Health Organization (WHO) has prioritized the infectious emerging diseases such as Coronavirus Disease (COVID-19) in terms of research and development of effective tests, vaccines, antivirals, and other treatments. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), the etiological causative agent of COVID-19, is a virus belonging to risk group 3 that requires Biosafety Level (BSL)-3 laboratories and the corresponding facilities for handling. An alternative to these BSL-3/-4 laboratories is to use a pseudotyped virus that can be handled in a BSL-2 laboratory for study purposes.
Recombinant Vesicular Stomatitis Virus (VSV) can be generated with complementary DNA from complete negative-stranded genomic RNA, with deleted G glycoprotein and, instead, incorporation of other fusion protein, like SARS-CoV-2 Spike (S protein). Accordingly, it is called pseudotyped VSV-SARS-CoV-2 S. In this review, we have described the generation of pseudotyped VSV with a focus on the optimization and application of pseudotyped VSV-SARS-CoV-2 S.
The application of this pseudovirus has been addressed by its use in neutralizing antibody assays in order to evaluate a new vaccine, emergent SARS-CoV-2 variants (delta and omicron), and approved vaccine efficacy against variants of concern as well as in viral fusion-focused treatment analysis that can be performed under BSL-2 conditions.

Aggressive Papillary Thyroid Carcinoma Presenting with Metastasis to the Pancreas

Papillary thyroid cancer is the most common type of thyroid cancer. Aggressive forms tend to metastasize to the lungs and bones, but the abdomen is a rare site of metastasis. We present a 46-year-old male patient who presented with a neck mass associated with shortness of breath and hemoptysis. He was found to have a large thyroid mass on imaging. He underwent a total thyroidectomy with bilateral neck dissection, with pathology showing a multifocal tall cell variant of papillary thyroid carcinoma with lymphovascular invasion in both thyroid lobes.
Due to recurrent findings of residual thyroid tissue on whole-body scan imaging, the patient underwent radioactive iodine ablation therapy twice, with poor response to therapy, suggested by persistently elevated thyroglobulin levels. However, the residual tissue responded to external beam radiation. After the initial response to radiation, thyroglobulin was noted to have increased again, prompting a PET-CT after administration of recombinant TSH. PET showed a focal area of increased uptake in the head of the pancreas.
The patient underwent the Whipple procedure for resection of the metastasis. Pathology showed papillary thyroid carcinoma with strong and diffuse staining for TTF-1 and thyroglobulin. The patient was started on lenvatinib in the postoperative period and is currently tolerating treatment well with evidence of decreasing thyroglobulin levels. Intra-abdominal metastasis from a thyroid malignancy source is quite rare and can be challenging as far as diagnosis and treatment. Surgical resection can be curative and can be followed by radioactive iodine ablation therapy if cancer cells show avidity. Tyrosine kinase inhibitors can be used in refractory disease. New research is being conducted on new agents that can reverse the resistance to radioactive iodine therapy.

Rat F actin capping protein subunit β(CAPZB) ELISA kit

192 tests 1524 EUR

Rat F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 48 wells 624 EUR

Rat F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 96 wells 822 EUR

Pig F actin capping protein subunit β(CAPZB) ELISA kit

192 tests 1524 EUR

Pig F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 48 wells 624 EUR

Pig F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 96 wells 822 EUR

Dog F actin capping protein subunit β(CAPZB) ELISA kit

192 tests 1524 EUR

Dog F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 48 wells 624 EUR

Dog F actin capping protein subunit β(CAPZB) ELISA kit

1 plate of 96 wells 822 EUR

Rat F actin capping protein subunit β(CAPZB) ELISA kit

96T 700 EUR

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