PHOSPHOFRUCTOKINASE (PFK) DEFICIENCY

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In addition to the erythrocytic pyruvate kinase deficiency, we have also established a colony of M-type PFK deficient dogs. These animals experience a chronic hemolytic anemia with alkaline induced hemolytic crises and exertional myopathy. The defect is caused by a premature stop codon leading to a truncation (loss of an alpha helix) and instability of the PFK protein. The lack of PFK activity in erythrocytes leads to impaired ATP and 2,3-diphosphoglyceride production and reduced survival of erythrocytes. We have established preliminary collaborations to investigate potential therapeutic interventions. Recent studies have shown that the administration of aminoglycosides may permit the read through an aberrant stop codon thereby permitting the production of the normal protein. Unfortunately, aminoglycosides are nephrotoxic particularly when used for longer periods of time and therefore they cannot safely be administered at the dose likely required. However, we have recently been approached by a company that has produced an analogue for which the safety in dogs has already been documented and a phase I clinical trial for children with cystic fibrosis is planned. Following in vitro testing in muscle cell cultures, we plan to perform a pilot study in the PFK deficient dogs and monitor the degree of hemolysis, red cell metabolites, hemoglobin-oxygen dissociation curve, alkaline fragility, and actual PFK activity in erythrocytes after administration. Furthermore, we have been approached by Richard Sabine, PhD, Associate Professor of Biochemistry from the Medical College of Wisconsin to collaborate in a feasibility study on the use of adenosine products to improve ATP and DPG production in PFK and PK deficient dogs prior to using this therapeutic approach in human patients with these and other diseases affecting ATP synthesis.