Proceedings from the Fourth International Symposium on sigma-2 receptors: Role in health and disease

The sigma-2 receptor (S2R) complex has been implicated in central nervous system disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer\u27s disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. Th

Carpenter-Coustan Compared With National Diabetes Data Group Criteria for Diagnosing Gestational Diabetes

Use of Carpenter-Coustan compared to National Diabetes Data Group (NDDG) criteria increases the number of women diagnosed with GDM by 30-50%, but whether treatment of this milder GDM reduces adverse outcomes is unknown. We explored the effects of the diagnostic criteria used on the benefits of GDM treatment

APOLLO: A randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic BRCA1, BRCA2 or PALB2 mutation-ECOG-ACRIN EA2192

Background: A meaningful subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with pathogenic variants in BRCA1, BRCA2 and PALB2. In the metastatic setting, PARP inhibitor maintenance provides a progression-free survival benefit after a period of platinum based chemotherapy1,2, but the role of PARP inhibitors in the curative intent setting is undefined. The OlympiA study established one year of olaparib as the standard of care for patients with BRCA-related, early stage breast cancer who completed all other curative-intent treatment3. Therefore, we have designed a randomized, phase II double-blind study of one year of olaparib vs placebo in patients with pancreatic cancer and a germline or somatic variant in BRCA or PALB2 who have completed all curative intent therapy. Methods: We have enrolled and treated 23 of 152 planned patients on study NCT 04858334/EA2192. Eligibility criteria include: a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 as determined by local laboratory (central review required); completion of curative-intent resection and ≥ three months of multi-agent chemotherapy; no evidence of recurrent disease. At enrollment, patients must be within 12 weeks of their last anti-cancer intervention. Patients are randomized 2:1 to receive oral olaparib 300 mg twice daily or placebo for 12 28-day cycles. The primary endpoint is relapse-free survival. Overall survival is a secondary endpoint. Tumor tissue, fecal material (for microbiome analysis) and serial ctDNA samples are being collected

The Clinical Promise of Biomarkers of Synapse Damage or Loss in Alzheimer’s Disease

BACKGROUND: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. CONCLUSION: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer\u27s disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer\u27s disease patients\u27 brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

Preclinical and clinical biomarker studies of CT1812:A novel approach to Alzheimer's disease modification

INTRODUCTION: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer’s disease (AD) patients’ brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812’s effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812’s impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APP(Swe)/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPP(Swe/Lnd+) and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18–26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812

Accounting for quality improvement during the conduct of embedded pragmatic clinical trials within healthcare systems: NIH Collaboratory case studies

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care

Does Maternal BMI Influence Treatment Effect in Women with Mild Gestational Diabetes?

To determine whether maternal body mass index (BMI) influences the beneficial effects of diabetes treatment in women with gestational diabetes (GDM)

Inadequate weight gain in overweight and obese pregnant women: what is the effect on fetal growth?

To evaluate inadequate gestational weight gain and fetal growth among overweight and obese women (O/O)

Delivery timing and cesarean delivery risk in women with mild gestational diabetes mellitus

To evaluate the relationship between gestational age (GA) and induction of labor (IOL) and the rate of cesarean delivery (CD) in women with mild gestational diabetes (GDM)