Robert Dunstan

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Small Molecule Mediated Inhibition of RORγ-Dependent Gene Expression and Autoimmune Disease Pathology In Vivo.

Retinoic acid receptor‐related orphan nuclear receptor γ (RORγ) orchestrates a pro‐inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ‐expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where RORγ expression is induced under specific pro‐inflammatory conditions, γδ T cells and other innate‐like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre‐existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ‐dependent gene expression programme in both Th17 cells and RORγ‐expressing γδ T cells as well as a disease‐relevant subset of human RORγ‐expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte‐driven mouse model of psoriasis.

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.

Molecular characterization and preclinical efficacy

Background: Passive immunotherapy with anti-Abeta antibodies is currently investigated for the treatment of Alzheimer’s Disease with several candidates in preclinical or clinical development. Methods: BIIB037 was generated using the Reverse Translational Medicine method (RTM). Binding properties of BIIB037 were measured in vitro against soluble and fibrillar Abeta. In vivo studies using Tg2576 mice were conducted to assess brain penetration and binding to amyloid plaques, as well as PK profile of the antibody. Preclinical efficacy was determined after chronic dosing using biochemical and histopathological endpoints. Results: BIIB037 is a fully human IgG1 monoclonal antibody derived from an AD patient with an unusual stable clinical course. The RTM approach was used to isolate, clone and recombinantly express the antibody. In vitro characterization shows a high affinity for insoluble fibrillar human Abeta using an ELISA format assay with fibrillar Abeta1-42 immobilized on the plate, and BIIB037 doesn’t bind to soluble Abeta1-40 in an inverted ELISA assay format. Binding was also evaluated using a TAPIR assay and staining of amyloid plaques in both AD brain and transgenic mice brain tissues was observed. BIIB037 enters the brain and binds to amyloid plaques after systemic administration in Tg2576 transgenic mice. The amount of drug detected into the brain is dosedependent. Chronic dosing for 6 months led to a significant amyloid load reduction as measured by ELISA and histopathology, but didn’t lead to increased plasma Abeta1-40, Abeta1-42 levels. Incidence of microhemorrhage and inflammation was not increased compared to vehicle treated group.Conclusions:A novel fully human antibody recognizing fibrillar human Abeta was characterized and its preclinical efficacy was demonstrated in vivo.

Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature21361

Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis.

Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease.

Quantitation of beta-amyloid in transgenic mice using whole slide digital imaging and image analysis software

the naturalhistory of small vessel diseases, evaluated in a large cohort of postmortem brains from the Newcastle Institute for Ageing and Health (Newcastle University, UK). This provides a score from 0 to 20 (no to severe vascular burden) and is in good agreement previous neuropathological standards. Nevertheless, the clinical relevance of this score has not yet been evaluated, and this was this study’s aim. Methods: Post mortem AD brains from Lille Neurobank (Lille, France) were scored according this cerebrovascular scale, blinded to clinical and neuroimaging data. Patients had been prospectively followed up with a standardized clinical examination, neuropsychological tests, and structural brain imaging. Correlation with the clinical diagnosis of vascular contribution, age at onset, disease duration, imaging white matter lesions visual scoring scale (Fazekas et al. 1987), vascular risk factors, Mini Mental State Examination score and Dementia Rating Scale score at first visit were analyzed with non-parametric tests. Results: Eleven patients were included. Four of them had a neuropathological cerebrovascular score < 10, all these 4 patients were clinically diagnosed as pure AD. Six of the 7 patients with a score 1⁄4 10 were considered to have no significant cerebrovascular contribution to their dementia. Higher scores were associated with a longer disease duration (p1⁄4 0.05) andtended to be associated with a higher Fazekas score.Conclusions: There is an urgent need to establish a reproducible and standardized quantitative assessment of the cerebrovascular burden in post mortem brains. In this small study, we used an original neuropathological cerebrovascular staging system which seems to be relevant enough to identify the clinical and imaging correlates of the cerebrovascular burden in clinicopathological series. In this limited number of cases, the clinical contribution of cerebrovascular lesions was largely underestimated. Further inclusions are needed to confirm our findings.