Enhancing Amyotrophic Lateral Sclerosis (ALS) drug discovery using physiologically relevant hiPSC-Derived Motor Neurons
Amyotrophic Lateral Sclerosis (ALS), a Motor Neurone Disease (MND) subtype is characterized by the degeneration and death of nerves (motor neurons) in the brain and the spinal cord that control essential voluntary muscle activity. Affecting over 400,000 patients worldwide each year , MND/ALS progressively causes difficulties in speaking, walking, breathing, and swallowing, with the disease eventually being fatal in about a quarter of all patients affected each year.
Traditionally, disease research and drug development has been based on animal-derived models of MND/ALS, usually involving studies of mouse models. Despite intensive research, there is currently no cure or standard treatment for these diseases. Riluzole and more recently, edaravone, are the only two drugs approved by the FDA, but they only reduce the progression of the MND/ALS in patients. Species specific differences between mouse models and human neurology is thought to be limiting our understanding of the pathological pathways underpinning MND/ALS. This reliance on animal-derived models is possibly curtailing, and even hindering, the translation of research findings into effective treatments.
As such, it is imperative to re-examine your current research models. Physiologically relevant human models, including patient-derived and corrected models of MND/ALS, are thought to be crucial to the advancement of proof-of-principle drug screening assays. This is now becoming a reality due to exciting progress in stem cell biology and the development of human induced pluripotent stem cell (hiPSC)-derived motor neurons.
Read on to find out why replacing your animal-derived models with hiPSC-derived motor neurons could advance the impact and translatability of your research, and potentially improve many patients’ quality of life.
Studying Motor Neurone Diseases: Why avoid animal models?
Research is now suggesting that the mouse models traditionally used in the study of MND/ALS, and for screening candidate compounds in drug development, is actually a poor representation of the human pathology. As such, there are increasing concerns about the validity of research based on animal-derived models, and the accuracy in which they can predict the effectiveness and toxicity of candidate drugs.
For example, doubts have arisen over past studies using transgenic mouse models of ALS, as only about 10% of ALS cases are familial in humans. Additionally, upper motor neuron (UMN) degeneration is a primary event in ALS pathology , because it impairs its important role (along with the corticospinal tract) in connecting the human cerebral cortex and spinal cord . However, UMNs do not play the same crucial role in mice .
This indicates that mouse models could reduce the accuracy of drug screening tests and the translatability of your research, causing a high drug development failure rate as well as increased risks and costs in downstream human clinical trials. Although the drawbacks of mouse models have prompted the development of new animal-derived model systems for ALS (e.g., Drosophila and zebrafish), the current lack of physiologically relevant human models is still limiting research translation and drug development.
How hiPSC-derived models can enhance Motor Neurone Disease research
In the quest for effective MND/ALS treatments, it is vital to use human models that accurately recapitulate the neurological pathways underpinning the disease (which we now know cannot be achieved using animal-derived models). Excitingly, hiPSC-derived motor neurons from both patients and healthy donors have recently been developed, offering a more physiologically relevant alternative to animal-derived models for in vitro experiments and drug screening.
For example, Axol’s hiPSC-Derived Motor Neuron Progenitors , from both a healthy male donor and a healthy male donor with a C9ORF72 extension (associated with familial ALS), are currently available and ready-to-use in your ALS research. Additionally, it will soon be possible to access hiPSC-derived Motor Neuron Progenitors from a female ALS patient donor with a C9ORF72 extension.
These hiPSC-derived motor neurons could help you uncover new breakthrough medicines for MND/ALS, due to their ability to offer more accurate screening assessments of candidate compounds in early drug discovery. Not only that, they will enable you to elucidate the pathogenesis of MND/ALS, which have proved difficult to investigate using animal-derived models.
Alongside these important research developments, you can also tap into new initiatives aiming to support and accelerate your drug development, including organizational frameworks that aim to share and coordinate research findings (e.g., TargetALS ).
Innovations arising from stem cell biology are providing promise and purpose in enhancing your research and drug development. Human iPSC-derived Motor Neuron Progenitors now offer the crucial toolkit you need to boost the physiological relevance and translatability of your in vitro studies. It is exciting to think that by leveraging this novel technology, we could uncover breakthrough insights into MND/ALS pathology and discover vital new medicines to improve the lives of many patients around the world.
Axol iPSCs were differentiated to motor neuron progenitors using a combination of small molecules to regulate multiple signalling pathways. Initial expansion of iPSC-Motor Neuron Progenitors is possible before the terminal differentiation to motor neurons.