Tracing investment in drug development for Alzheimer disease

Kodamullil, Alpha Tom; Zekri, Firas; Sood, Meemansa; Hengerer, Bastian; Canard, Luc; McHale, Duncan; Hofmann‐Apitius, Martin

doi:10.1038/nrd.2017.169

Cited by 48 publications

(32 citation statements)

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“…5j) is 22 MCI due to AD patients and 22 healthy subjects. A diagnosis of MCI was based on the following criteria, which were adapted from the MCI diagnostic criteria of Petersen: (1) memory complaints, preferably corroborated by a spouse or relative; (2) Stained cells were washed twice with PBS. Cells were acquired using FACS Fortessa X-20 flow cytometer (BD Biosciences, San Jose, CA).…”

Section: Human Subjectsmentioning

confidence: 99%

“…Despite the tremendous efforts made in the treatment of Alzheimer's disease (AD), the past decades have witnessed the continuous failure of β-amyloid (Aβ)-or tau-centric therapeutic strategies in late-stage clinical trials, which impels the reconsideration of new therapeutic strategy for this complicated disease. 1,2 Recently, a plethora of studies have shown the dynamic interaction between the intestinal microbiota and host innate and adaptive immune system. 3,4 The dysbiosis of gut microbiota could jeopardize host immune responses and promote the development of various inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

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Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Wang¹,

et al. 2019

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Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

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Section: Human Subjectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Wang¹,

et al. 2019

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“…The FDA approved only four therapeutics in that time leaving a lot to learn from past failures. Neuroprotective DMTs made up 34% of the therapeutics discontinued in this time, leaving in their wake a plethora of lessons that can be applied to upcoming therapeutics [21]. A shift in development from the conventional small molecule drug (SMD) to a biological approach has shown benefits.…”

Section: Lessons From Previous Clinical Trialsmentioning

confidence: 99%

An Alternate View of Neuroprotection with Peptides in Alzheimer’s Disease

King¹,

Suphioglu²

2020

Neuroprotection - New Approaches and Prospects

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Neuroprotection plays a crucial role in everyday life, maintaining a clean environment in the central nervous system to allow for normal functioning. In Alzheimer's disease and other neurodegenerative disorders, neuroprotection may have two roles. Under standard circumstances, the immune system protects the CNS, but sometimes it can exacerbate the pathophysiology of some diseases through neuroinflammation leading to further degeneration. Alzheimer's disease is fast getting out of control, with no new approvals in therapeutics since 2003, and of those approved, all target symptomatic treatment. Initiated by a microglial response to Aβ plaques, therapeutic development should focus on the amyloid cascade as a neuroprotective measure for Alzheimer's disease. This chapter will examine the status of the types of therapeutics in clinical trials for Alzheimer's disease, offering insights into peptides as an area of opportunity for neuroprotection and detailing considerations for the use of peptides in Alzheimer's disease.

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“…In addition to cognitive decline, AD patients have extensive neuropathological changes including deposition of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal death (2,3). It is estimated that the number of AD patients will reach 16 million by 2050 in the United States alone (4,5). Effective treatments are needed, as there are no disease-modifying treatments for AD and no new drugs have been approved since 2003 by the US Food and Drug Administration (FDA).…”

Section: Introductionmentioning

confidence: 99%

AlzGPS: A Genome-wide Positioning Systems Platform to Catalyze Multi-omics for Alzheimer’s Therapeutic Discovery

Zhou

Fang

Bekris

et al. 2020

Preprint

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BackgroundOver15 million family members and caregivers have expended $220 billion for care of patients with AD and other dementias, and the attrition rate for AD clinical trials (2002-2012) is estimated at 99.6%. While recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, no effective disease-modifying or preventive therapies, for AD have emerged in the past two decades. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor.MethodsIn this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer’s Therapeutic Discovery, https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and effective prevention and treatment of AD.ResultsVia AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecules’ profiles underlying AD pathogenesis (e.g., early vs. late stage and tau vs. amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we identified repurposable drugs from ∼3,000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated 300 literature references for highly repurposable drugs; (5) we included information from over 200 ongoing AD clinicals noting drug mechanisms and primary drug targets, and linking them to our integrated multi-omics view for targets and network analyses results for the drugs; (6) we implemented a highly interactive web-interface for database browsing and network visualization.ConclusionsNetwork visualization enabled by the AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for data sets-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, the AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.

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Tracing investment in drug development for Alzheimer disease

Cited by 48 publications

References 0 publications

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

An Alternate View of Neuroprotection with Peptides in Alzheimer’s Disease

AlzGPS: A Genome-wide Positioning Systems Platform to Catalyze Multi-omics for Alzheimer’s Therapeutic Discovery

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