A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Right ventricular assessment in patients undergoing transcatheter or surgical aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative treatment option to surgical aortic valve replacement (SAVR) in selected high-risk patients. In this study, we aimed to evaluate the prognostic value of right ventricular (RV) functional imaging to predict clinical response to TAVR and SAVR. METHODS: One hundred and ten patients with symptomatic severe aortic valve stenosis (AVS) undergoing successful TAVR and 32 controls undergoing SAVR were prospectively enrolled. Six months follow up (FU) included two-dimensional (2D) transthoracic echocardiography (TTE) with RV deformation imaging. RESULTS: Baseline TTE showed no significant differences between groups (TAVR and SAVR) in conventional left ventricular (LV) and RV functional parameters (LV ejection fraction [LV-EF]: p = .21; tricuspidal annular plane systolic excursion [TAPSE]: 1.8 ± 0.5 cm, 1.9 ± 0.4 cm, p = .21), and RV strain (right ventricular-global longitudinal strain [RV-GLS] -11.6 ± 5.2%, -11.5 ± 6.5%, p = .70). At FU LV function was unchanged in both groups (p > .05); RV function was significantly improved after TAVR (RV-GLS: -11.6 ± 5.2%, -13.4 ± 6.1%, p = .005; TAPSE: 1.8 ± 0.5 cm, 1.9 ± 0.3 cm, p = .05), and worsened after SAVR (RV-GLS: -11.5 ± 6.5%, -8.9 ± 5.2%, p = .04; TAPSE: 1.9 ± 0.4 cm, 1.5 ± 0.3 cm, p < .001). Functional New York Heart Association (NYHA) class remained unchanged in patients after SAVR (p = .21), and improved after TAVR (p < .001). Baseline RV function was linked with clinical response to TAVR (TAPSE, p < .0001; RV-GLS, p = .04), and the development of RV-GLS was associated with functional worsening after SAVR (p = .05). CONCLUSION: Baseline RV function and changes of right heart mechanics are closely associated with functional improvements after AVR. SAVR, but not TAVR, seems to have detrimental effects on RV-function.

A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis.

Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.

High-speed video gait analysis reveals early and characteristic locomotor phenotypes in mouse models of neurodegenerative movement disorders.

Neurodegenerative diseases of the central nervous system frequently affect the locomotor system resulting in impaired movement and gait. In this study we performed a whole-body high-speed video gait analysis in three different mouse lines of neurodegenerative movement disorders to investigate the motor phenotype. Based on precise computerized motion tracking of all relevant joints and the tail, a custom-developed algorithm generated individual and comprehensive locomotor profiles consisting of 164 spatial and temporal parameters. Gait changes observed in the three models corresponded closely to the classical clinical symptoms described in these disorders: Muscle atrophy due to motor neuron loss in SOD1 G93A transgenic mice led to gait characterized by changes in hind-limb movement and positioning. In contrast, locomotion in huntingtin N171-82Q mice modeling Huntington's disease with basal ganglia damage was defined by hyperkinetic limb movements and rigidity of the trunk. Harlequin mutant mice modeling cerebellar degeneration showed gait instability and extensive changes in limb positioning. Moreover, model specific gait parameters were identified and were shown to be more sensitive than conventional motor tests. Altogether, this technique provides new opportunities to decipher underlying disease mechanisms and test novel therapeutic approaches.

Reduced ß-amyloid pathology in an APP transgenic mouse model of Alzheimer's disease lacking functional B and T cells.

INTRODUCTION: In Alzheimer's disease, accumulation and pathological aggregation of amyloid ß-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain ß-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer's disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice. RESULTS: Analyses from both experimental approaches revealed reduced ß-amyloid pathology and decreased brain amyloid ß-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain ß-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid ß-peptide aggregates. CONCLUSION: The results of this study demonstrate an impact of the adaptive immunity on cerebral ß-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid ß-peptide clearance as a possible underlying mechanism.

Amyloid-ß peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

Passive immunization with anti-amyloid-ß peptide (Aß) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aß-specific DARPins. We further showed their ability to delay Aß aggregation and prevent Aß-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aß-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aß levels. These findings demonstrate the therapeutic potential of Aß-specific DARPins for the treatment of Alzheimer disease.