AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.     

Serum alarm antiproteases in systemic sclerosis patients

Alarm antiproteases, i.e. secretory leukocyte protease inhibitor ad elafin, are key mediators in innate immune response and integrate innate and adaptive immunity systems. The aim of the study was to assess clinical significance of serum levels of alarm antiproteases, elafin and secretory leukocyte protease inhibitor (SLPI) in patients with systemic sclerosis (SSc). Twenty-eight patients with SSc, 25 patients with rheumatoid arthritis (RA) and 22 healthy controls were recruited. Serum elafin and SLPI levels were examined using enzyme-linked immunosorbent assay (ELISA). The patients with SSc had significantly increased serum levels of SLPI in comparison with the RA patients and the healthy controls (p < 0.01), and the RA patients presented significantly higher serum levels of elafin in comparison with the controls (p = 0.003). In the SSc subgroup serum SLPI level negatively correlated with diffusing capacity of the lung for carbon monoxide (DLCO) (r = ?0.41, p = 0.03) and total lung capacity (r = ?0.42, p = 0.03). Both alarm antiproteases, elafin and SLPI could be potentially implicated in the pathogenesis of SSc and SLPI may be considered a candidate for serum biomarker of lung involvement in SSc.     

Clinical options after failure of allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies

Disease recurrence is the single most common cause of death after allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Disease status and chemosensitivity at the time of transplantation, as well as the development of graft-versus-host disease (GVHD), are factors known to influence the risk of relapse post-HSCT. Both acute and chronic GVHD have been associated with decreased relapse rates; however, owing to toxicity, overall survival is not consistently improved in these patients. Furthermore, there is a transient period of immunodeficiency after HSCT, which may permit residual malignant cells to proliferate early in the post-transplant course, before the donor immune system can establish a graft-versus-tumor response. Patients who fail an initial HSCT have an extremely poor outcome; therefore, maneuvers to prevent, identify and treat recurrent disease as early as possible in these situations are necessary. Strategies to distinguish graft-versus-tumor from GVHD, to enhance both general and disease-specific immune reconstitution after transplantation, and to increase donor-mediated anti-host immune reactions are being investigated in clinical trials. Single agent nontoxic post-HSCT chemotherapy, cellular therapies and second allogeneic HSCT using reduced intensity regimens are among the modalities under investigation.     

Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes.

Both serotonin transporter and brain-derived neurotrophic factor (BDNF) genes have been previously implicated in the efficacy of lithium prophylaxis. The aim of the present study was to assess a possible interaction between serotonin transporter genotype (5HTTLPR) and BDNF Val66Met polymorphism, and the prophylactic response to lithium. The study was performed on 111 patients with bipolar mood disorders (43 male, 68 female), aged 30-77 (mean 54 years) who have been treated with lithium carbonate for at least 5 years (5-27 years, mean 15 years). In the group studied, 31 patients (28%) were classified as excellent responders (ER), 54 (49%) as partial responders (PR), and 26 (23%) as non-responders (NR) to lithium prophylaxis. Age at onset of the illness, duration of illness before treatment introduction and on lithium as well as number of affective episodes before lithium treatment did not differ between these three subgroups of patients. A significant interaction between BDNF and 5HTTLPR polymorphism and lithium response was found. S individuals (patients with s/s or s/l genotype) having Val/Val genotype were significantly more frequent in NR compared with ER or/and PR. Also, S individuals showed extreme differences in response to lithium prophylaxis depending on having either Val/Val or (Val/Met + Met/Met) genotypes of BDNF polymorphism: 9/48 (19%) of ER and 18/48 (37%) of NR in the first group, and 12/30 (40%) and 1/30 (3%) in the second group, respectively. The results obtained may show a significant epistatic interaction between 5-HTTLPR and BDNF polymorphism, and response to lithium prophylaxis.