Advances in Therapeutics for Neurodegeneration - ALS Flashcards
Neurodegenerative diseases
The most common neurodegenerative disease is Alzheimer’s Disease (AD), affecting 900,000 (1.3%) people in the UK.
This is followed by:
- Parkinson’s Disease - 153,000
- Multiple Sclerosis - 130,000
- Huntington’s Disease - 7,000
- Amyotrophic Lateral Sclerosis (ALS) - 5,000
This is out of a population of 67 million in 2021.
As a rare disease is defined as ‘less than 1 in 2,000 (0.05%)’, this will include Huntington’s Disease and ALS.
Drugs aimed at treating neurodegenerative diseases have particularly poor progress in clinical trials, having a higher failure rate - industry average is 14.6 failed drugs for every drug on the market, but for AD there are 119.3 failed drugs for every successful one.
Despite this, many major pharmaceutical companies continue to invest in drug discovery for neurodegeneration, including these ‘rare’ diseases.
Tissue and molecular levels
All neurodegenerative diseases involve progressive damage of the nervous system.
However, they affect different areas of the NS, contributing to different symptoms.
- Alzheimer’s Disease (AD) affects the hippocampus, impairing memory
- Amyotrophic Lateral Sclerosis (ALS) affects the motor pathway down the spinal cord, impairing muscle control
Similarities between neurodegenerative diseases at the molecular level can be memorised using the acronym ‘DOPING’ and include:
- Death of neurons and reduced trophic support. Trophic support is the maintenance of neurons through trophic factors, which are proteins that promote cell survival, growth, and differentiation.
- Oxidative stress, energy metabolism
- Protein aggregation and aberrant turnover
- Inflammation, altered glial function
- Neurotransmission: glutamate excitotoxicity
- Genetics: impaired DNA and RNA homeostasis
There are distinctions in which proteins are aggregated and which genes are dysregulated between different diseases.
For example, in Alzheimer’s disease, the gene encoding the amyloid precursor protein (APP) is dysregulated and amyloid β and tau proteins aggregate.
By contrast, in amyotrophic lateral sclerosis, many genes can be dysregulated; most cases are sporadic, however these often have the same genetic abnormalities as familial cases. Proteins such as superoxide dismutase 1 (SOD1) can aggregate.
- SOD1 aggregation is also seen with frontotemporal dementia - shared pathology.
Biomarkers and early detection
Many neurodegenerative diseases would benefit from earlier detection.
Biomarkers could be detected in the cerebrospinal fluid (CSF).
In AD, amyloid β pathology is detected before tau phosphorylation, and many years before changes in the tissue or clinical symptoms.
Other ‘out of the box’ indicators are also being explored, such as changes in artwork.
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease (USA), is the most common form of motor neuron disease. ALS is also called ‘jian dong ren’ = gradually frozen men (China).
Symptoms include muscle cramps, worsening weakness, difficulty swallowing and eventually respiratory issues which can lead to death.
Median onset of 60 years old.
Median survival is 4 years but patients can survive up to 20. Famous exception: Stephen Hawking - diagnosed at 21, lived with it for >50 years.
In clinical trials, muscle function is assessed using the Revised ALS Functional Rating Scale (ALSFRS-R).
ALS involves degeneration of motor neurons in the corticospinal tract. Both upper and lower motor neurons are affected.
Sensory neurons are spared.
Control of the eye and anal sphincter are one of the final regions of motor control remaining in patients. Stephen Hawking used eye tracking technology to communicate.
Pathology is also observed in the astrocytes and microglia.
ALS at the molecular level
ALS is polygenic, implicating SOD1, as well as TDP-43/FUS and 20+ other genes, such as neurofilament genes.
There is aggregation of SOD1, involved in neutralizing ROS, leading to mitochondrial dysfunction. This causes oxidative stress.
- SOD1 is an antioxidant protein, converting superoxide to hydrogen peroxide and oxygen. Mutants form aggregates, decreasing zinc binding and disturbing the structure of intermediate filaments.
- Autosomal dominant mutations are associated with 10-20% of familial and 1-2% of sporadic cases.
There is also formation of stress granules containing TDP-43/FUS, an RNA-binding protein regulating mRNA expression, such as BDNF expression.
Excessive glutamate neurotransmission occurs, leading to neuronal death, with reduced neurotrophic factors.
Microglial activation occurs, leading to the release of inflammatory mediators.
There is a higher incidence of ALS in the Pacific island Guam, later termed ‘Guam ALS’, due to ingestion of BMAA from cyanobacteria.
BMAA is a glutamate analogue that acts as an agonist for NMDA and AMPA ion channels.
Reducing excitotoxicity - Riluzole
Riluzole, approved in 1995, reduces glutamate excitotoxicity by inhibiting excessive neurotransmitter release.
It has a complex mechanism of action modulating a range of ion channels.
One major component is blocking presynaptic Na+ channels, therefore reducing the release of glutamate.
It has some effect on prolonging survival by ~3-6 months but a limited ability to improve symptoms.
Protecting from free radicals - Edaravone
Edaravone is an antioxidant drug that scavenges free radicals, protecting from ROS.
As a result, it scavenges oxidative stressors released from degenerating motor neurons.
It was originally developed for acute ischemic stroke.
It is still not approved in Europe, despite gaining approval in the US in 2017, due to a lack of efficacy.
Increases survival by ~6 months.
**Sodium Phenylbutyrate and Taurursodiol are also used to slow the progression. They reduce ER stress and mitochondrial dysfunction.
Monoclonal antibody α-miSOD1
AP-101 is a recombinant human IgG1 antibody that selectively binds the misfolded and aggregated SOD1 protein, promoting clearance.
It is currently in Phase II clinical trials.
Familial ALS participants must demonstrate SOD1 mutation to benefit from this drug.
It is comparable to Lecanemab for Alzheimer’s disease binding amyloid β, where antibody binding promotes clearance through immune responses.
AP-101 is administered intravenously. However, biologics struggle to cross the BBB, so upper motor neurones may not benefit.
Gene therapy - Tofersen
Tofersen is an antisense oligonucleotide (ASO), a single-stranded nucleic acid directed at the RNA encoding SOD1.
It acts to downregulate SOD1 mRNA, therefore reducing synthesis of the protein.
Approved by the FDA in 2023.
Not yet approved by EMA, currently in Phase III clinical trials for patients with SOD1 mutations.
Kinase inhibitors for microglial activation - Sotuletinib
Sotuletinib is a brain-penetrant kinase inhibitor, blocking the colony stimulating factor receptor (CSF1R).
It targets microglia, the primary immune cells of the central nervous system, reducing their proliferation. It therefore reduces neuroinflammation.
It’s currently in Phase II clinical trials
The drug also being tested in patients with advanced solid tumours.
Using neurotrophic growth factors - Engensis
Glial cell-derived neurotrophic factor (GDNF) is a growth factor for motor neuron survival.
Directed delivery of GDNF has a limited effect due to short plasma half-life and poor BBB penetration (intrathecal or subcutaneous).
Engensis involves the delivery of a plasmid encoding hepatocyte growth factor (HGF), a 728 aa protein.
HGF plays a role in nerve cell growth, survival, and regeneration.
This is injected directly into muscles
Engensis has just finished Phase II trials
The drug is also being tested in patients with painful diabetic neuropathy, Charcot-Marie-Tooth Disease Subtype 1A (CMT1A) and chronic non-healing foot ulcers.
Using stem cells - Lenzumestrocel
Lenzumestrocel (Neuronata-R) are bone marrow-derived mesenchymal stem cells (BM-MSC).
This uses autologous cells, where pluripotent cells taken from a patient’s bone marrow are transplanted via intrathecal injection.
The cells are immunomodulatory with anti-inflammatory and neuroprotective effects
The therapeutic is currently in Phase III trials and already approved in South Korea.
There are some regulatory cautions with unethical clinics linked to ‘stem cell tourism’.
Stem cell therapies are more common for the treatment of blood disorders.
Using growth factors and stem cells
Stem cells can be modified to secrete additional neurotrophic growth factors.
CNS10-NPC-GDNF are modified stem cells.
Neural progenitor cells (NPCs) are transduced with glial cell-derived neurotrophic factor (GDNF) and differentiated into astrocytes.
CNS10 indicates ‘clinical grade’
The cells are transplanted into the spinal cord, but 50% of patients developed pain.
These are currently in Phase I/2a trials, delivering directly into the motor cortex
Another example is NurOwn, mesenchymal stem cell neurotrophic factor (MSC-NTF) cells, created using autologous bone marrow–derived MSCs to secrete high levels of NTFs in addition to their well-documented intrinsic immunomodulatory properties.
Progress in treating neurodegenerative diseases
Improved biomarkers are needed.
Possible biomarkers for ALS include:
- Neurofilament Light Chain (NfL) can be detected in cerebrospinal fluid and blood. It is released when neurons are damaged, but also in Alzheimer’s disease, multiple sclerosis etc.
- TDP-43, although the aggregated form rarely enters cerebrospinal fluid and blood.
To benefit, earlier detection should be accompanied by disease-modifying therapy.
Heterogeneity of diseases like ALS means that multi-target therapy is likely to be needed.
Genome sequencing can be beneficial, allowing personalised medicine to be used - e.g. some therapeutics are only beneficial in ALS if the SOD1 mutation is present.
There are economical limitations, particularly considering that current drugs have a limited effect beyond extending survival. Even Riluzole has financial implications, costing the NHS up to £7.5 million/year, and stem cells are much more expensive.
