Disease-modifying Therapeutics Research Articles

Aging, cellular senescence and Parkinson's disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1–2% of people over age 65. The risk of developing PD dramatically increases with advanced age, indicating that aging is likely a driving factor in PD neuropathogenesis. Several age-associated biological changes are also hallmarks of PD neuropathology, including mitochondrial dysfunction, oxidative stress, and neuroinflammation. Accumulation of senescent cells is an important feature of aging that contributes to age-related diseases. How age-related cellular senescence affects brain health and whether this phenomenon contributes to neuropathogenesis in PD is not yet fully understood. In this review, we highlight hallmarks of aging, including mitochondrial dysfunction, loss of proteostasis, genomic instability and telomere attrition in relation to well established PD neuropathological pathways. We then discuss the hallmarks of cellular senescence in the context of neuroscience and review studies that directly examine cellular senescence in PD. Studying senescence in PD presents challenges and holds promise for advancing our understanding of disease mechanisms, which could contribute to the development of effective disease-modifying therapeutics. Targeting senescent cells or modulating the senescence-associated secretory phenotype (SASP) in PD requires a comprehensive understanding of the complex relationship between PD pathogenesis and cellular senescence.

New Research on Biomarkers in Alzheimer's Continuum.

Alzheimer's disease (AD) is a multifactorial pathology, responsible for neurodegenerative disorders which in more than 60% of patients evolve into dementia. Comprehension of the molecular mechanisms underlying the pathology and the development of reliable diagnostic methods have made new and more effective therapies possible. In recent years, in addition to the classic anticholinesterases (AChEs), which can control the clinical symptoms of the disease, compounds able to reduce deposits of amyloid-β (Aβ) and/or tau (τ) protein aggregates, which are disease-modifying therapeutics (DMTs), have been studied. The results have shown that symptomatic therapy works best when administered in the disease's mild to moderate clinical phase. On the other hand, treatment with DMTs has been found to be more effective in the preclinical stage of AD, when Aβ and τ protein neurofibrillary tangles have not yet been compromised and patients still have a normal quality of life. This innovative approach requires the identification of specific biomarkers predictive of the disease, detectable many years before clinical signs are evident. Biomarkers allow early diagnosis, give indications of the possible development of dementia in the future, and make it possible to study the evolution of the disease. New scenarios, involving different pathways and approaches, could emerge and provide effective therapies to treat the very early stages of the disease and hamper its progression. The specific biomarkers studied so far have been reported here.

Cardiac involvement in systemic sclerosis: A critical review of knowledge gaps and opportunities.

Cardiovascular complications are observed in up to one-third of patients with systemic sclerosis (SSc). Early identification and management of SSc-associated primary cardiac disease is often challenging, given the complex disease pathophysiology, significant variability in clinical presentation, and scarce disease-modifying therapeutics. Here, we review the molecular mechanisms involved in SSc-associated cardiac disease pathogenesis, novel diagnostic tools and emerging therapies.

Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease

Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with clinical data from our previously published phase 2 proof-of-concept study, support the potential of APOL1 channel inhibition for the treatment of AMKD.

Prioritizing Parkinson's disease risk genes in genome-wide association loci.

Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging. Our aim was to prioritize genes underlying PD GWAS signals. The polygenic priority score (PoPS) is a similarity-based gene prioritization method that integrates genome-wide information from MAGMA gene-level association tests and more than 57,000 gene-level features, including gene expression, biological pathways, and protein-protein interactions. We applied PoPS to data from the largest published PD GWAS in East Asian- and European-ancestries. We identified 120 independent associations with P < 5×10-8 and prioritized 46 PD genes across these loci based on their PoPS scores, distance to the GWAS signal, and presence of non-synonymous variants in the credible set. Alongside well-established PD genes (e.g., TMEM175 and VPS13C), some of which are targeted in ongoing clinical trials (i.e., SNCA, LRRK2, and GBA1), we prioritized genes with a plausible mechanistic link to PD pathogenesis (e.g., RIT2, BAG3, and SCARB2). Many of these genes hold potential for drug repurposing or novel therapeutic developments for PD (i.e., FYN, DYRK1A, NOD2, CTSB, SV2C, and ITPKB). Additionally, we prioritized potentially druggable genes that are relatively unexplored in PD (XPO1, PIK3CA, EP300, MAP4K4, CAMK2D, NCOR1, and WDR43). We prioritized a high-confidence list of genes with strong links to PD pathogenesis that may represent our next-best candidates for disease-modifying therapeutics. We hope our findings stimulate further investigations and preclinical work to facilitate PD drug development programs.

ALZpath pTau217: Multi‐cohort performance, cross‐assay comparison, and clinical launch for the identification of Alzheimer’s Disease pathology

AbstractBackgroundBlood‐based AD biomarker tests will be essential clinical tools to provide accessible and affordable screening and monitoring for AD disease‐modifying therapeutics (DMT) as well as advancing overall clinical care. Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer’s disease (AD) pathology using blood. We describe a multi‐cohort evaluation of the Simoa ALZpath pTau217 assay in plasma, including memory clinic patients, as well as performance in the context of other commercially available pTau217 assays. Finally, we discuss the clinical launch of ALZpath pTau217 including pTau217 reference intervals and clinical cutoffs in the context of other pTau217 assays.MethodThe ALZpath pTau217 assay is an ultra‐sensitive blood‐based test developed on the semi‐automated single‐molecule array Simoa platform; it is the first commercially available pTau217 test and has been used in over 40 cohort studies with over 50,000 sample tests. To enable clinicians to leverage ALZpath pTau217 to inform care decisions, ALZpath Dx has been validated in partnership with Neurocode CLIA‐certified laboratory.ResultWe discuss multi‐cohort ALZpath pTau217 findings for the prediction of amyloid and tau burden, measured using PET imaging and post‐mortem histology. In a pTau217 cross‐assay evaluation, ALZpath pTau217 had the strongest relationship with amyloid load as measured by (PiB) PET in a population of healthy and MCI individuals in comparison with other blood‐based AD biomarker assessments including the integration of multiple biomarkers. We discuss pTau217 reference intervals derived from multiple normative populations and compare pTau217 levels detected across multiple pTau217 assays, demonstrating that reference intervals are currently highly assay specific, highlighting the importance of efforts underway to develop a pTau217 reference standard. Finally, we report the clinical launch of ALZpath Dx, including pTau217 clinical cutoffs derived from cross‐cohort analyses, and the implications for the dementia clinical care system.ConclusionMulti‐cohort findings support ALZpath pTau217 as a high performing diagnostic biomarker for Alzheimer’s disease with high accuracy in determining amyloid burden across all stages of AD continuum. ALZpath pTau217 performance capabilities can support timely AD identification and intervention and facilitate scalable DMT implementation.

Recent Advances in Therapeutics for the Treatment of Alzheimer's Disease.

The most prevalent chronic neurodegenerative illness in the world is Alzheimer's disease (AD). It results in mental symptoms including behavioral abnormalities and cognitive impairment, which have a substantial financial and psychological impact on the relatives of the patients. The review discusses various pathophysiological mechanisms contributing to AD, including amyloid beta, tau protein, inflammation, and other factors, while emphasizing the need for effective disease-modifying therapeutics that alter disease progression rather than merely alleviating symptoms. This review mainly covers medications that are now being studied in clinical trials or recently approved by the FDA that fall under the disease-modifying treatment (DMT) category, which alters the progression of the disease by targeting underlying biological mechanisms rather than merely alleviating symptoms. DMTs focus on improving patient outcomes by slowing cognitive decline, enhancing neuroprotection, and supporting neurogenesis. Additionally, the review covers amyloid-targeting therapies, tau-targeting therapies, neuroprotective therapies, and others. This evaluation specifically looked at studies on FDA-approved novel DMTs in Phase II or III development that were carried out between 2021 and 2024. A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.

Unraveling the thrombin–Alzheimer’s connection: Oral anticoagulants as potential neuroprotective therapeutics

In Alzheimer&amp;rsquo;s disease (AD), toxic amyloids formed by amyloid-&amp;beta; (A&amp;beta;) proteins and tau are implicated in the development of inflammatory, vascular, and neurodegenerative brain disorders. Thrombin has also been recognized as a proteopathic factor involved in A&amp;beta;-induced neurovascular dysfunction. Vascular A&amp;beta; activates the contact system in the blood, stimulating the production of inflammatory bradykinin and procoagulant thrombin. Thrombin, in turn, triggers inflammation, platelet activation, and the formation of fibrinolysis-resistant, A&amp;beta;-containing fibrin clots, leading to A&amp;szlig;-type cerebral amyloid angiopathy and associated neuropathology. Targeting thrombin with oral anticoagulants can normalize proinflammatory and prothrombotic states, counteracting the neurovascular consequences of AD. Pre-clinical studies have shown that such interventions preserve vascular and blood&amp;ndash;brain barrier integrity, improve cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of toxic A&amp;beta;, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory and neurodegenerative processes, ultimately preserving cognitive functions for a longer period. Recent observational clinical studies in patients with atrial fibrillation (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-users. The anti-dementia effects were most prominent in elderly patients but were also observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs reduced the risk of intracranial hemorrhage by approximately 50% compared to VKAs. The current review highlights the potential neuroprotective role of DOACs in AD. By preventing excessive thrombin generation caused by A&amp;beta; pathology, DOACs could protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation for their potential repurposing as disease-modifying therapeutics in AD.

12380 Point Of Care Microscale Magnetic Resonance (µNMR) Effectively Monitors Mitigation Of Oxidative Stress By GLP-1 Treatment In A Preclinical Model Of Diabetic Nephropathy

Abstract Disclosure: A.T. Alves: ; co-founder. ; LarmorBio. S.S. Thamarath: ; co-founder. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-founder. ; LarmorBio. R. Rohr: ; co-founder,CEO. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. Oxidative stress is a major driver in the pathogenesis of diabetes, obesity, and related (cardio-renal) disorders. Early detection and prevention of an oxidative stress overload can improve and potentially modify the long-term harmful outcomes associated with chronic hyperglycaemia. A novel assay was developed, that uses µNMR technology to directly monitor oxidative stress from 5 µL of plasma at the point of collection in less than 10 minutes. This assay is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation and lipid peroxidation. Here, we show the oxidative stress profiling of three groups of ZSF1 rats in a twelve week (11th -23rd week of age) observational study. Vehicle lean, vehicle obese, and glucagon-like-peptide-1 (GLP-1) treated obese ZSF1 rats (n = 8/group) were studied with the assay along with conventional diabetic/metabolic markers, blood glucose (BG), HbA1c, Albumin Creatinine Ratio (ACR). The kidney (immuno)histology studies, alpha-smooth muscle actin (aSMA) and leucocyte common antigen (CD45) were performed at the termination phase of the ZSF1 rats (23rd week of age). The results demonstrated that the assay distinguished obese rats from lean rats with statistical significance (P ≤ 0.01) independent of other in-life diabetic/metabolic markers. Significant correlations with urinary Albumin Creatinine Ratio (ACR, ρ = 0.64, P ≤ 0.0001) were established throughout the study. A positive quantitative association is highlighted with classic histological end points of organ damage, kidney fibrogenesis (aSMA, ρ = 0.23), and inflammation (CD45, ρ = 0.45). Moreover, the assay detected significantly reduced oxidative stress levels (e.g., P ≤ 0.01) in the GLP-1 drug treatment group at five weeks of follow-up. In summary, the µNMR assay effectively monitored oxidative stress and captured disease-modifying therapeutics. Presentation: 6/1/2024

The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core: An update.

Biomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease-modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non-AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential. We conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases. Clinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co-pathologies. These results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co-pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non-AD neuropathologies. The ADNI NPC supports this mission with well-characterized tissue samples (available through ADNI and the National Institute on Aging) and "gold-standard" diagnostic information (soon to include digital histology). The Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases. ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging. Digitized slide files from the ADNI NPC will be available in 2025. Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation. Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology. Neuropathology is essential for the development of novel AD/ADRD biomarkers.

Risk willingness in multiple system atrophy and Parkinson’s disease understanding patient preferences

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson’s Disease (PD) are in early phases of clinical testing. Involving patients’ preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001–25%] of sudden death for a 99% [interquartile range: 99.999–75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001–5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients’ risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients’ risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.

Teaming up to overcome challenges toward translation of new therapeutics for osteoarthritis.

As a leading global cause of musculoskeletal-related disability, osteoarthritis (OA) represents a public health urgency. Understanding of disease pathogenesis has advanced substantially in the past decade, yet no disease-modifying therapeutics have advanced to the clinic. To address this challenge, the CARE-AP (Cartilage Repair strategies to alleviate Arthritis Pain) collaborative research team was convened to bring together relevant multidisciplinary expertise and perspectives from across the VA research community nationwide. The first CARE-AP Annual Research Symposium took place (virtually) in February 2022 with roughly 90 participants. A number of innovative and therapeutic strategies were discussed, including siRNA approaches coupled with novel nanoparticle-based delivery systems, cellular engineering approaches to develop reparative cells that can probe the joint environment and respond to disease-specific cues, and novel biofabrication techniques to improve tissue engineering and effect "biological joint replacement." In addition, challenges and advances in rehabilitation approaches, imaging outcomes, and clinical studies were presented, which were integrated into a framework of recommendations for running "preclinical trials" to improve successful clinical translation.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials. We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering. We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering. CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain. CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09. CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism. Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.

Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves.

Charcot-Marie-Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine-to-proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early-onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data-independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3-week-old, age and genetic strain-matched wild-type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography-mass spectrometry (LC-MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p-value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality-controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome-lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage-associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease-modifying therapeutics that could be effective for distinct neuropathies.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer’s Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3',5'-monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease-modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.

A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease

BackgroundEffective, disease-modifying therapeutics for the treatment of Alzheimer’s disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among the most toxic forms of Aβ. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aβ oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aβ oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients.MethodsThe present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration.ResultsNo treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated.ConclusionsThe safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development.Trial registrationThe clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).

Clinical Meaningfulness in Alzheimer's Disease Clinical Trials. A Report from the EU-US CTAD Task Force.

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.

Phenylstyrylpyrimidine derivatives as potential multipotent therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide. Despite extensive research efforts, there are currently no effective disease-modifying therapeutics available for the complete cure of AD. In the current study, we have designed and synthesized a series of phenyl-styryl-pyrimidine derivatives as potential multifunctional agents against different targets of AD. The compounds were evaluated for their ability to inhibit acetylcholinesterase (AChE), monoamine oxidase (MAO) and β amyloid aggregation which are associated with the initiation and progression of the disease. Several compounds in the series exhibited potent inhibitory activity against AChE and MAO-B, with IC50 values in the low micromolar range. In particular, two compounds, BV-12 and BV-14, were found to exhibit a multipotent profile and showed non-competitive inhibition against MAO-B with IC50 values of 4.93 ± 0.38 & 7.265 ± 0.82 μM, respectively and AChE inhibition with IC50 values of 7.265 and 9.291 μM, respectively. BV-12 and BV-14 also displayed β amyloid self-aggregation inhibition of 32.98% and 23.25%, respectively. Furthermore, molecular modelling studies revealed that BV-14 displayed a docking score of -11.20 kcal mol-1 with MAO-B & -6.767 kcal mol-1 with AChE, forming a stable complex with both proteins. It was concluded that phenyl-styryl-pyrimidine derivatives have the potential to be developed as multitarget directed ligands for the treatment of AD.