Novartis And Axovant Might Jointly Be Holding The Most Promising Neurodegeneration Drug In Development

Novartis And Axovant Might Jointly Be Holding The Most Promising Neurodegeneration Drug In Development

Publication date: Jun 06, 2019

Nilotinib, a tyrosine kinase inhibitor developed by Novartis (NYSE:NVS) and approved for leukemia treatment as Tasigna, is being tested in a phase-2 trial for treating AD.

Nilotinib can inhibit multiple tyrosine kinase receptors, including c-ABL, EphA4, DDR1, PDGFRα/β.

First, Nilotinib inhibits the tyrosine kinase c-ABL, which is activated in AD dystrophic neurites.

Supporting this is the finding of significantly decreased gliosis and reduced escape latency in the Morris water maze in an AD mouse model treated with imatinib, a broad tyrosine kinase inhibitor of cABL (similar to Nilotinib), compared to untreated controls.

Corroborating the potential antioxidant effect, ST1571, a broad tyrosine kinase inhibitor that also inhibits c-ABL, inhibited H O -mediated apoptosis in cultured hippocampal neurons and Nilotinib treatment reduced oxidative stress in a rat model of liver toxicity.

The macroautophagy defect in AD and PD, however, occurs mostly in distal axons, where a profound accumulation of autophagosomes and autophagic vacuoles accumulate in axonal swellings, which is thought to be caused by defective lysosomal digestion or defective autophagosomes transport from the distal axon to the proximal axon and cell body where lysosomal acidification and bulk digestion occurs.

Moreover, in AD brain, many autophagy transcripts are upregulated and the neuron body has the appearance of overactive autophagy with depleted organelles, such as mitochondria, which could be reflective of autophagic programmed cell death.

Chaperone-mediated autophagy degrades strictly old proteins, such as α-synuclein, tau, and amyloid, and is dependent on two proteins, which are reduced in brain regions from PD patients, but not from AD.

EphA4 is activated by β-amyloid oligomers, the toxic fragments that accumulate in AD, and the association of SORLA with EphA4 significantly reduces β-amyloid-mediated EphA4 activation in cultured cortical neurons and in mouse hippocampus injected with β-amyloid.

DDR1 is expressed in oligodendrocytes and endothelial cells, and its expression is increased in AD brain.

Collagen activated DDR1 can up-regulate metalloproteinase 9 (MMP-9), which can degrade basement membrane, leading to compromised integrity of the brain blood barrier (BBB), an early biomarker of AD.

However, blocking DDR1 signaling in oligodendrocytes could prevent MMP-9 mediated myelin protein degradation that leads to white matter lesions in AD.

MMP-9 is increased in AD extracellular matrix, presumably through DDR1 activation, and increased MMP-9 can degrade nerve growth factor leading to the loss of trophic support needed for cell survival and maintenance.

In sum, Nilotinib-mediated DDR1 inhibition could decrease MMP-9 levels, thereby reducing MMP-9-mediated degradation myelin proteins, NGF, collagen VI, and additionally, reduce collagen-mediated microglia activation.

Concepts Keywords
ABL Leukemia treatment
Action Potential Microtubules network
Alzheimer Apoptosis
Amyloid Pharmacokinetics
Antioxidant Protein kinase inhibitor
Apoptosis Receptor tyrosine kinase
Apoptotic Tyrosine kinase inhibitor
Autophagic Nilotinib
Autophagy Tyrosine kinase receptors
Axon Imidazoles
Axonal Transport Pyrimidines
Axons Enzymes
Biotech Pyridines
Brain Chemical compounds
Catalase Branches of biology
Chaperone Cognitive impairment
Clustering Organelles Macroautophagy dysfunction
Cognitive Impairment Inflammatory microglia activation
Cortical Chronic myeloid leukemia
Degenerate Symptoms fatigue
Dendrites PDGFR ischemic stroke
Digestion BBB permeability inflammation
Distal Diseases
Fibrils HIV
Flux Nilotinib leukemia
Frontal Cortex Leukemia
Glia Neurocognitive disorders
Gliosis Diagnosis broader treatment
Growth Cone
Hippocampal
Hippocampus
Huntington
Hydrogen Peroxide
Hyperphosphorylation
Imatinib
Latency
Leukemia
Ligand
Liver Toxicity
Lyn
Lysosomal
Macroautophagy
Membrane Receptor
Mice
Microtubule
Microtubules
Mitochondria
Morris Water Maze
Mutation
Neurites
Neurodegeneration
Neuron
Neurons
Nilotinib
Normalized
Novartis
NYSE
Oligomers
Organelles
Oxidative Damage
Oxidative Stress
Parkinson
Pathogenesis
Pathology
PDGFR
Phase 2 Trial
Phosphorylates
Phosphorylation
Protein
Proximal
Reactive Oxygen Species
Receptor
Receptor Tyrosine Kinase
Receptors
Substrate
Substrates
Synaptic
Tyrosine Kinase
Tyrosine Kinase Inhibitor
Tyrosine Kinase Receptors
Vacuole
Vacuoles

Semantics

Type Source Name
gene UNIPROT FASTK
gene UNIPROT PTPN5
gene UNIPROT CEP55
gene UNIPROT CFLAR
gene UNIPROT SORBS1
gene UNIPROT SERPINB6
gene UNIPROT BRD4
gene UNIPROT HACD1
gene UNIPROT LNPEP
gene UNIPROT CAP1
disease MESH diagnosis
disease DOID dementia
disease MESH dementia
disease DOID neurodegeneration with brain iron accumulation
disease DOID multiple system atrophy
disease MESH multiple system atrophy
gene UNIPROT ARTN
disease DOID dementia with Lewy bodies
gene UNIPROT AGRP
disease DOID synucleinopathies
pathway BSID Chronic myeloid leukemia
disease DOID chronic myeloid leukemia
disease MESH opportunistic infections
drug DRUGBANK Hydrocortisone
disease MESH infection
pathway BSID Gene Expression
drug DRUGBANK Nerve Growth Factor
pathway BSID Release
disease MESH inflammation
gene UNIPROT ATAT1
disease MESH neurocognitive disorders
gene UNIPROT TAT
disease MESH hemorrhage
gene UNIPROT NGF
gene UNIPROT MMP9
gene UNIPROT APP
gene UNIPROT LYN
disease MESH cognitive impairment
gene UNIPROT SORL1
disease MESH death
drug DRUGBANK Water
disease MESH gliosis
gene UNIPROT MAPT
gene UNIPROT CDK5
gene UNIPROT PDGFRB
gene UNIPROT DDR1
gene UNIPROT EPHA4
gene UNIPROT ABL1
drug DRUGBANK L-Tyrosine
disease MESH multiple
gene UNIPROT DNER
disease DOID leukemia
disease MESH leukemia
drug DRUGBANK Nilotinib
disease MESH Development
gene UNIPROT LARGE1
pathway BSID Programmed Cell Death
pathway BSID Macroautophagy
pathway BSID Apoptosis
pathway BSID Oxidative Stress
disease MESH oxidative stress
drug DRUGBANK Imatinib
drug DRUGBANK L-Arginine
gene UNIPROT ABL2
gene UNIPROT RERE
pathway BSID Oxidative Damage
drug DRUGBANK Hydrogen peroxide

Leave a Comment

Your email address will not be published. Required fields are marked *