Dataset Information

Improving Molecular Therapy in the Kidney.

ABSTRACT: Mutations in approximately 80 genes have been implicated as the cause of various genetic kidney diseases. However, gene delivery to kidney cells from the blood is inefficient because of the natural filtering functions of the glomerulus, and research into and development of gene therapy directed toward kidney disease has lagged behind as compared with hepatic, neuromuscular, and ocular gene therapy. This lack of progress is in spite of numerous genetic mouse models of human disease available to the research community and many vectors in existence that can theoretically deliver genes to kidney cells with high efficiency. In the past decade, several groups have begun to develop novel injection techniques in mice, such as retrograde ureter, renal vein, and direct subcapsular injections to help resolve the issue of gene delivery to the kidney through the blood. In addition, the ability to retarget vectors specifically toward kidney cells has been underutilized but shows promise. This review discusses how recent advances in gene delivery to the kidney and the field of gene therapy can leverage the wealth of knowledge of kidney genetics to work toward developing gene therapy products for patients with kidney disease.

SUBMITTER: Rubin JD

PROVIDER: S-EPMC7367759 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Improving Molecular Therapy in the Kidney.

Rubin Jeffrey D JD Barry Michael A MA

Molecular diagnosis & therapy 20200801 4

Mutations in approximately 80 genes have been implicated as the cause of various genetic kidney diseases. However, gene delivery to kidney cells from the blood is inefficient because of the natural filtering functions of the glomerulus, and research into and development of gene therapy directed toward kidney disease has lagged behind as compared with hepatic, neuromuscular, and ocular gene therapy. This lack of progress is in spite of numerous genetic mouse models of human disease available to t ...[more]

PMID: 32323260

Similar Datasets

Project description:Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such "high-resolution" detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.

Project description:This quality improvement project was conducted at the haemodialysis unit in the paediatric nephrology department at Noah's Ark Children's Hospital, Cardiff. Stakeholders involved were the medical and nursing staff at the haemodialysis unit, responsible for the care of children with chronic kidney disease CKD. Anaemia is prevalent among children with CKD. Iron infusion is administered to such children with chronic anaemia. Children on haemodialysis attending the Children's Kidney Center receive iron infusion if they satisfy the criteria based on haemoglobin and serum ferritin values according to departmental guidelines. This involves measurement of c-reactive protein and serum ferritin prior to iron administration. High iron exposure is detrimental to end organ function and hence warrants regular monitoring in conjunction with CRP, another inflammatory marker. We suspect that some children may be receiving iron infusions despite being iron replete. Also, we may be over-investigating these children with anaemia. We identified all children receiving iron infusion in the haemodialysis unit over a four week period. We retrospectively enquired blood investigations done, prior to and after iron infusion. Blood investigations lagged on pre and post infusion times. We devised a checklist for nursing staff to follow, primarily looking at set times for measuring haemoglobin, serum ferritin, and CRP during the month (at the start of the first and third week of the month) and also tabulating the ferritin values that would trigger frequency of iron infusions. These were aimed to: 1. Prevent iron overloading in patients with chronic anemia 2. Regularise the checking of bloods in those receiving iron infusions 3. Empower the nursing staff to independently take decisions on iron infusion delivery. The strategy for change encompassed multiple PDSA cycles. Plan: empower decision making on iron infusion by haemodialysis nursing staff Do: formulate a checklist for iron infusion based on the recommended set values of ferritin, CRP and haemoglobin Study: analyse adherence to checklist in three months time Act: make appropriate changes to workplace behaviour based on findings of the PDSA cycle We analysed 13 patient episodes prior to the intervention and a total of 19 patient episodes after the improvement cycles. The checklist was improved based on feedback obtained after the first PDSA cycle. A second cycle showed that investigations done were optimised. The third cycle showed improved adherence and compliance with prevention of over-treatment with iron infusion. There was 100% adherence to the investigations done prior to infusion and complied well with the department guidelines. This meant that the required number of blood tests were done on a more regular basis and it did not exceed from those done previously. Nursing behaviour with regard to initiation and maintenance of iron infusion became more independent. This empowered nursing decision making skills and consequently freed doctor-time. It also resulted in improving team morale and ultimately patient safety by mitigating human errors. For any QI project, interventions should be carefully designed. Stakeholder buy-in and easy accessibility of the intervention improves sustainability. Multiple PDSA cycles and incorporating stakeholder feedback into the cycle are key to success.

Dataset Information

Improving Molecular Therapy in the Kidney.

Publications

Improving Molecular Therapy in the Kidney.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets