Pharmaceuticals & Biologics
The invention includes methods of preventing and reversing prefrontal cortical decline in normal aged subjects by providing a protein kinase C inhibitor to the subject. The protein kinase C inhibitor can be a phenanthridinium alkaloids or other closely related compound. The inventors have found that when such compounds are administered to normal aged subjects the cognitive performance, including including performance in tasks that utilizing working memory, of the subjects improves.
Yale scientists have discovered that the level of IL-18 and its downstream targets were increased in patients with COPD, as well as in the lungs of smokers. Furthermore, it was found that treating mice with antibody against IL-18Rα significantly decreased Cigarette Smoke (CS) - induced inflammation. IL-18 signaling contributes to the pathogenesis of CS-induced emphysema, pulmonary inflammation and apoptosis. Therefore, the levels of circulating IL-18 represent a readily accessible biomarker for the diagnosis of COPD, and blocking IL-18Rα would be an effective therapy against COPD.
Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.
The recent discovery of a role for SEMA 7A in fibrosis using mouse models provides a new therapeutic target for the treatment of fibrosis in lung disease and may be suitable for the treatment of other fibrotic diseases.
Frontotemporal dementia (FTD) is known to be caused by loss of function mutations in the secreted protein progranulin but the physiological role of progranulin the brain is not known. Yale investigators found that Progranulin binds the cell surface protein Sortilin as a receptor. Progranulin/sortilin interaction regulates BDNF secretion. Thus, sortilin receptor agonists are predicted to ameliorate deficits in Fronto-Temporal dementia.
In a collaborative study, Yale researchers have developed a novel DNA-based diagnostic that detects mutations in ion channels in patients presenting with hypertension due to primary aldosteronism (PA). Somatic mutations cause increased sodium ion conductance, cell depolarization, and intracellular calcium levels have been revealed in 47% of sporadically occurring aldosterone-producing adenomas. This test may eliminate the requirement for the conventional, yet invasive, adrenal vein sampling, thereby streamlining the diagnostic evaluation of severe hypertension. Furthermore, this technology can indicate a direct diagnosis for a surgically correctable form of the disease, in which an adrenalectomy can cure hypertension and correct hypokalemia in the large majority of patients with increased aldosterone due to PA. Most importantly, this genetic test can be used as a stand-alone or a companion diagnostic in all patients with worsening or difficult-to-treat hypertension leading to markedly improved care and reduced overall costs. In addition to this, antibody therapy could be developed to inhibit or decrease the mutated potassium channel activity, and thereby present a new therapeutic option for treatment of this patient group
Yale investigators have developed a new synthetic platelet to treat hemorrhage. The synthetic platelet resembles the shape of an activated platelet (star burst) and is made from FDA-approved materials, consisting of a nanosphere core and polyethylene glycol (PEG) arms. Our synthetic platelet is capable of forming a barrier to reduce membrane permeability and enhance the sealing on a disrupted blood vessel wall, which is extremely beneficial to promote synthetic platelet aggregation at the site of injury.
Researchers at Yale University have identified a pharmacological mechanism whereby proliferation of oligodendrocytes can be stimulated by activation of ATP-dependent potassium channels (KATP channel) in the plasma membranes of oligodendrocytes. Small molecular weight candidate therapeutic compounds (e.g., Diazoxide) have been identified which activate the KATP channel and which have been shown not only to promote proliferation of oligodendrocyte precursor cells in culture but also to increase myelination in rat brain slices in vitro and to prevent hypomyelination and ventriculomegaly in vivo in newborn mice subjected to chronic sub-lethal hypoxia. One of the KATP channel activators shown to mediate the effect on myelination has also been used therapeutically in infants to treat hyperinsulinemic hypoglycemia.
Yale researchers have discovered a novel method of stimulating arterial collateral growth by simultaneous activation of both the Raf1/ERK and PI3K/Akt signaling pathway, a result not typically seen in adult cells, mimicking embryonic arteriogenesis. Specifically, ERK activation is achieved by introducing RAF1 mutant resistant to inhibition by PI3K/Akt signaling. Representative microCT images show increased artery development after treatment with GS4898 (an ERK activator), similar results are expected from ongoing mouse experiments with simultaneous activation of both Raf1/ERK and PI3K/Akt signaling.
A novel tetrodotoxin resistant sodium channel is described, along with isolated nucleotides that encode this receptor. Methods for identifying agents that modulate the Na.sup.+ current through the receptor are provided, as well as related therapeutic and diagnostic methods.