A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Effects of Multiple Dose Regimens of CHF 5074 for up to 2 Years on Potential Biomarkers of Neurodegeneration in Subjects With Mild Cognitive Impairment

To evaluate the effects of multiple dose regimens of CHF 5074 administered once per day up to 2 years on potential biomarkers of neurodegeneration in subjects with mild cognitive impairment.

Start Date01 Dec 2012

Sponsor / Collaborator

Cerespir, Inc.

NCT01303744

/ CompletedPhase 2

A Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Tolerability of Multiple Dose Regimens of CHF 5074 and to Explore the Effects in Patients With Mild Cognitive Impairment

To evaluate the safety and tolerability of ascending oral doses of CHF 5074 administered once per day for up to 12 weeks to patients with mild cognitive impairment.

Start Date01 Mar 2011

Sponsor / Collaborator

Cerespir, Inc.

NCT01258452

/ CompletedPhase 1

Randomized, Balanced, Single Dose, Cross-Over Study to Evaluate the Effects of Food Ingestion on the Pharmacokinetics of CHF 5074 in Healthy Young Male Subjects

To evaluate the effects of a high-calorie high-fat meal on the extent and rate of absorption of CHF 5074 after single oral administration in young healthy male volunteers.

Start Date01 Feb 2011

Sponsor / Collaborator

Cerespir, Inc.

100 Clinical Results associated with Cerespir, Inc.

0 Patents (Medical) associated with Cerespir, Inc.

Literatures (Medical) associated with Cerespir, Inc.

23 Aug 2022·Science Signaling

The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson’s disease

Article

Author: Chia, Sook Yoong ; Jiang, Mei ; Chain, Daniel G. ; Zhou, Zhi-Dong ; Ling, Shuo-Chien ; Jang, Se-Eun ; Ma, Dong-Rui ; Zhang, Zhi-Wei ; Yu, Wei-Ping ; Tan, Eng-King ; Guo, Kai-Hua ; Zeng, Li ; Ong, Zhi-Wei ; Margolin, Richard A. ; Vanan, Sarivin ; Xu, Jie ; Saw, Wuan-Ting ; Tu, Haitao

Gain-of-function mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene are common in familial forms of Parkinson’s disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of β-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2 G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2 G2019S mice. In LRRK2 G2019S mice or cultured dopaminergic neurons from LRRK2 G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.

26 Jan 2018·Central Nervous System Agents in Medicinal Chemistry

Basic Approaches in Therapy of Multiple Sclerosis (MS) and Related Diseases: Current Achievement and Prospective

Review

Author: Skundric, Dusanka S

INTRODUCTIONThis overview is aimed at reevaluating fundamental approaches of current MS therapies with focus being placed on their targeted underlying immune, molecular and cellular mechanisms. Currently used therapies are discussed in regard to their mechanisms of action, clinical accomplishments and unwanted side effects and complications. Special emphasis is given to the current first generation Disease Modifying Therapies (DMT) and their actions at immune mechanisms of disease. Effects of DMT on CD4+Th1 cells and their associated cytokines and signaling pathways are discussed in more detail.CONCLUSIONAttention is paid to emerging role of a CD4 T cell chemotactic cytokine, IL-16 in regulation of relapsing MS and its model, experimental autoimmune encephalomyelitis (EAE). Immune mechanisms mediated by IL-16 are critically evaluated in the context of mechanisms of DMT and its potential as prospective MS therapy. In relation to clinical assessment of therapy, existing and prospective molecular biomarkers are highlighted and discussed where applicable.

Alzheimer's Research & TherapyQ2 · MEDICINE

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

Q2 · MEDICINE

ArticleOA

Author: Soares, Holly ; Huang, Yafei ; Chen, Xia ; Das, Ujjwas ; Slats, Diane ; Lucey, Brendan P ; Margolin, Richard ; Dean, Robert A ; Sjögren, Magnus ; Savage, Mary J ; Forman, Mark ; Kennedy, Matthew ; Li, Jinhe ; Tong, Gary ; Waring, Jeffrey F ; Slemmon, J Randall ; Farlow, Martin R ; Bateman, Randall J ; Siemers, Eric R ; Fox, Gerard B ; Gonzales, Celedon ; Claassen, Jurgen A H R ; Verbeek, Marcel M

AbstractIntroductionAmyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time.MethodsGrouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time.ResultsAnalysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors’ studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection.ConclusionsBased on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors’ studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.

100 Deals associated with Cerespir, Inc.

100 Translational Medicine associated with Cerespir, Inc.

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