Current and Future Therapeutics for Treating Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.

Motion Characterization of Pacemaker Lead Wire In Vivo for Piezoelectric Energy Harvesting Applications.

PURPOSE: Piezoelectric energy harvesters (PEH) for cardiac pacemakers typically use animal models to assess the performance of the PEH. However, if considering multiple designs, the use of animal models and prototyping increases costs and time. To reduce the use of animal models in research for pacemaker energy harvesting applications, this study investigates the motion of a pacemaker lead wire (PLW) in vivo using fluoroscopy imaging to quantify the position and displacements as a function of time, such that the data can be used in computer simulations. METHODS: The proposed technique uses fluoroscopy imaging video data of a dual chamber pacemaker implanted in a patient, and image processing allows for the motion of the PLW captured. The motion is discretized into nodes for ease of implementation in finite element software. FEA simulation is presented using a piezoelectric energy harvester design integrated in the lead wire, and the energy output is predicted by finite element computer simulation. RESULTS: A 2-dimensional analysis is conducted with the fluoroscopy imaging video data to characterize the PLW motion and results show close agreement with literature values. Simulations with an energy harvesting circuit using the nodal position and displacement data shows that a PEH integrated in the PLW can generate a direct current voltage of 1.12 V and power output of 0.125 µW, potentially extending the battery life of pacemakers by 0.75-1 years. CONCLUSIONS: The results suggest that fluoroscopy imaging data can be effective in evaluating PEH designs rather than using animal models, saving time and costs.

Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.

Successful drug discovery requires accurate decision making in order to advance the best candidates from initial lead identification to final approval. Chemogenomics, the use of genomic tools in pharmacology and toxicology, offers a promising enhancement to traditional methods of target identification/validation, lead identification, efficacy evaluation, and toxicity assessment. To realize the value of chemogenomics information, a contextual database is needed to relate the physiological outcomes induced by diverse compounds to the gene expression patterns measured in the same animals. Massively parallel gene expression characterization coupled with traditional assessments of drug candidates provides additional, important mechanistic information, and therefore a means to increase the accuracy of critical decisions. A large-scale chemogenomics database developed from in vivo treated rats provides the context and supporting data to enhance and accelerate accurate interpretation of mechanisms of toxicity and pharmacology of chemicals and drugs. To date, approximately 600 different compounds, including more than 400 FDA approved drugs, 60 drugs approved in Europe and Japan, 25 withdrawn drugs, and 100 toxicants, have been profiled in up to 7 different tissues of rats (representing over 3200 different drug-dose-time-tissue combinations). Accomplishing this task required evaluating and improving a number of in vivo and microarray protocols, including over 80 rigorous quality control steps. The utility of pairing clinical pathology assessments with gene expression data is illustrated using three anti-neoplastic drugs: carmustine, methotrexate, and thioguanine, which had similar effects on the blood compartment, but diverse effects on hepatotoxicity. We will demonstrate that gene expression events monitored in the liver can be used to predict pathological events occurring in that tissue as well as in hematopoietic tissues.