Advances in therapeutics for neurodegeneration Flashcards
Prevalence and drug discovery limitations
Highly prevalent, with 900,000 with AD in the UK. 150,000 with PD, 130,000 with MS.
Huntingtons and ALS are considered rare as less the 1 in 2000 have it.
There is a very high failure rate in drugs for neurodegenerative diseases compared to industry averages, with particularly high failure in the preclinical stage. despite this there is continued investment in drug discovery for neurodegeneration.
Molecular and tissue pathology
Sees progressive damage to the nervous system with different regions affected depending on the disease. e.g., AD affecting the hippocampus (memory) and ALS affecting motor pathways down the spine.
The hallmarks of neurodegeneration is death of neurones, oxidative stress, protein aggregation/abberent turnover, inflammation, altered neurotransmission, altered glial function, altered genetic homeostasis.
Differences in protein aggregation depending on disease, e.g., amyloid precursor protein mutation in AD leading to amyloid-B plaques. Tau proteins also seen in AD.
In ALS see lots of genes involved, with superoxide dismutase 1 (SOD1) protein being the driving factor.
These biomarkers can be detected in the cerebrospinal fluid, however, this detection is often too late. Amyloid-B pathology can be detected before Tau phosphorylation and many years before tissue or clinical changes in the patient with AD. Other means of identifying the diseases are being explored, such as changes in artwork in AD.
Many of these biomarkers are non-specific, such as neurofilament light chain. difficult for early detection.
Pathology of ALS
The most common motor neuron disease. causes cramps, weakness, difficulty swallowing and respiratory issues. 3-5y after onset death is common.
See degeneration of upper and lower motor neurones in the corticospinal tract, but does not affect sensory neurones. Eyes and anal sphincter are one of the final regions where muscle control is retained.
the pathology can also be observed in astrocytes and microglia. microglia activation leads to inflammatory mediator release.
SOD1 strongly implicated alongside TDP-43/FUS and 20+ there genes. the aggregation of SOD1 (which neutralises ROS) leads to mitochondrial dysfunction. this leads to the formation of stress granules that contain TDP-43/FUS and RNA-binding protein that regulates mRNA expression. this leads to glutamatergic excitotoxicity and reduced neurotrophic factors (e.g., BDNF).
Approved drugs for ALS
Riluzole blocks presynaptic sodium channels to reduce the release of glutamate - reduces excitotoxicty. only has limited effects in prolonging survival (3-6m) with little ability to improve symptoms. approved in 1995.
edaravone is an antioxidant that scavenges ROS. reduces the oxidative stressors released from degenerating motor neurones. originally developed for acute ischaemic stroke. approved in the USA in 2017
Targeting SOD1
AP-101 (phase 2 trial) is a recombinant human IgG1 antibody that selectively binds to misfolded and aggregated SOD1. IV administration. similar mechanism to lecanemab which binds to amyloid-B for treatment of AD.
Tofersen (phase 3 trial) is an antisense oligonucleotide (single-stranded nucleic acid) directed at the RNA that acts to downregulate SOD1 mRNA. only for patients that have SOD1 mutations. Only 10-20% have mutations in familial cases, and only 1-2% in sporadic.
Targeting microglia in ALS
Sotuletinib (phase 2) blocks colony stimulating factor receptor (CSF1R) in microglia to reduce inflammation.
CSFR1 needed for microglial development.
Targeting neurotrophic growth factors and use of stem cells in ALS
Glial cell-derived neurotrophic factor (GDNF) is a growth factor for motor neurone survival, however only has limited effect due to poor BBB penetration and short t1/2
engensis (phase 2) is a drug that delivers a plasmid encoding hepatocyte growth factor (HGF). it is directly injected into muscles. HGF is a potent survival-promoting factor in motor neurones. also being tested for diabetic neuropathy
Lenzumestrocel (phase 3 but approved in south korea) is bone marrow-derived mesenchymal stem cells. it is obtained from the same individual (autologous). these cells are immunomodulatory with anti-inflammatory and neuroprotective effects. would be transplanted via spinal (intrathecal) injection.
CNS10-NPC-GDNF combines stem cells and growth factors. Neural progenitor cells (NPC) are transducer with GDNF and are differentiated into astrocytes. they are then transplanted into the spinal cord. this however leads to 50% of patients developing pain. in phase 1/2a trials for being delivered directly to the motor cortex
Iimitation of stem cells in their price
