A Phase 1, Randomized, Double-Blind, Placebo-Controlled, SAD and MAD Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral FB418 in Healthy Adult Subjects and Healthy Elderly Subjects

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of oral doses of FB418 in healthy adult subjects and healthy elderly subjects.

Start Date01 Dec 2023

Sponsor / Collaborator

1st Biotherapeutics, Inc.Startup

100 Clinical Results associated with LRRK2 x ABL1

100 Translational Medicine associated with LRRK2 x ABL1

0 Patents (Medical) associated with LRRK2 x ABL1

Literatures (Medical) associated with LRRK2 x ABL1

01 Dec 2023·Ageing Research Reviews

Exploring Parkinson-associated kinases for CRISPR/Cas9-based gene editing: beyond alpha-synuclein

Review

Author: Mansour, Heba M ; El-Khatib, Aiman S

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substania nigra (SN) and is associated with progressive motor impairment. PD is classified into familial and sporadic forms. The first genetic association studies in PD reported the involvement of Synuclein alpha (SNCA) mutations in the pathobiology of familial PD. Subsequent studies suggested mutations in PTEN-induced putative kinase 1 (PINK1), PARKIN, leucine repeat kinase-2 (LRRK2), and DJ-1 causing familial PD. In addition, kinase dysregulation has been embroiled in the pathogenesis of PD. The genome-editing mechanism CRISPR (clustered regularly interspaced short palindromic repeats) has recently influenced industry and scientific discoveries and is expected to expedite neurodegenerative disease research. This review will discuss the structure, function, and history of the CRISPR/Cas9 genome editing system. Moreover, it summarizes genes-encoding kinases involved in PD pathogenesis and targeted by CRISPR/Cas9 technology, including LRRK2, PINK1, Protein kinase C-delta (PKC-γ), and adenosine monophosphate-activated protein kinase (AMPK). We provide an overview of novel kinases to be targeted by the CRISPR/Cas9 system such as G-protein coupled receptor kinases (GRKs), cyclin-G-associated kinases (GAKs), cyclin-dependent kinase 5 (CDK5), Ataxia telangiectasia mutated (ATM), c-ABL, and rearranged during transfection (RET) receptors. Additionally, we will explain the off-target effects of CRISPR/Cas9 system and how to address them. Also, we will shed light on the associated challenges and future directions that are enabling the efficient use of CRISPR/Cas9 technology in kinases research in PD. In conclusion, gene editing, in addition to gene therapy, might be a possible promising strategy for PD therapy.

01 Nov 2023·Food and Chemical Toxicology

Pazopanib ameliorates rotenone-induced Parkinsonism in rats by suppressing multiple regulated cell death mechanisms

Article

Author: Mansour, Heba M ; Mohamed, Ahmed F ; El-Khatib, Aiman S ; Khattab, Mahmoud M

Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.

01 Sep 2023·European Journal of Pharmacology

Lapatinib ditosylate rescues motor deficits in rotenone-intoxicated rats: Potential repurposing of anti-cancer drug as a disease-modifying agent in Parkinson's disease

Article

Author: Mansour, Heba M ; F Mohamed, Ahmed ; El-Khatib, Aiman S ; Khattab, Mahmoud M

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits induced by dopaminergic neuronal death in the substantia nigra (SN). Finding a successful neuroprotective therapy is still challenging despite improved knowledge of the etiology of PD and a variety of medications intended to reduce symptoms. Lapatinib (LAP), an FDA-approved anti-cancer medication, has been stated to exert its effect through the modulation of oxidative stress. Furthermore, recent studies display the neuroprotective effects of LAP in epilepsy, encephalomyelitis, and Alzheimer's disease in rodent models through the modulation of oxidative stress and ferroptosis. Nevertheless, it is questionable whether LAP exerts neuroprotective effects in PD. In the current study, administration of 100 mg/kg LAP in rotenone-treated rats for 21 days ameliorates motor impairment, debilitated histopathological alterations, and revived dopaminergic neurons by increasing tyrosine hydroxylase (TH) expression in SN, along with increased dopamine level. LAP remarkably restored the antioxidant defense mechanism system, GPX4/GSH/NRF2 axis, inhibiting oxidative markers, including iron, TfR1, PTGS2, and 4-HNE, along with suppression of p-EGFR/c-SRC/PKCβII/PLC-γ/ACSL-4 pathway. Moreover, LAP modulates HSP90/CDC37 chaperone complex, regulating many key pathological markers of PD, including LRRK2, c-ABL, and α-syn. It is concluded that LAP has neuroprotective effects in PD via modulation of many key parameters implicated in PD pathogenesis. Taken together, the current study offers insights into the potential repositioning of LAP as a disease-modifying drug in PD.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis