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Beyond Symptom Relief: Human iPSC-derived Models for the Development of Life-changing Therapies for Neurodegenerative Diseases

The complexity and epidemiology of neurodegenerative diseases demands the incorporation of alternative approaches for the development of disease-modifying therapies that can bring real improvements to patients. iPSC-derived models are based on human biology offering unique characteristics which are greatly benefiting early and preclinical drug development. In this editorial we discuss the status of drug discovery and development for Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS), focusing on promising candidates identified with the help of iPSC technology.


Neurodegenerative diseases (NDDs) are a heterogeneous group of diseases characterised by progressive neuronal cell death that leads to gradual loss of motor, sensory and/or cognitive functions. Most available treatments for NDDs only attempt to alleviate symptoms or slow disease progression, rather than the root cause of the disease. Meanwhile the incidence of these diseases is rising dramatically due to increased life expectancy and aging population, creating an urgent need for disease-modifying therapies.1

The FDA estimates that for every new drug approved for NDDs, approximately 40 have failed in clinical trials, of which many were initially seen as highly promising2 in preclinical settings. One of the main reasons for this high risk of failure is the “translational gap”: drugs that work during preclinical testing often fail to show efficacy or present safety issues in clinical trials.3 Interspecies differences between animal models typically used for preclinical testing and humans, greatly contribute to this translational gap. In addition, sparse understanding of the genetic and mechanistic basis of neurodegenerative diseases hampers the identification of key targets with the capacity to really modify the disease. Although there have been significant advancements in this area, the complexity of the brain and the lack of access to neuronal human tissue has hindered further progress.3

Under these circumstances, there seems to be a clear need to explore alternative approaches to better facilitate target identification and advance therapeutics with higher confidence throughout the pipeline.

The Value of Human iPSCs in Drug Discovery

In early drug discovery models relying on immortalised cells are commonly used, as they are relatively simple to culture, amenable to scale up for high-throughput screening and present a relatively low cost. These models have helped advance drug discovery for decades but have repeatedly shown to have limited physiological relevance and reproducibility. Primary human cells and tissues offer an alternative to address those challenges, as they are physiologically relevant and can help understand disease pathology and the impact of potential therapeutic candidates. Unfortunately, lack of access to those materials, especially neuronal cells, as well as difficulty keeping them in culture for useful periods of time prevent primary cells from being a viable option for high-throughput applications.3 Preclinical testing is usually performed on animal models. Using complex organisms allow for the assessment of behaviour, cognition, and physiology providing valuable information about disease mechanisms as well as drug safety. Nonetheless, interspecies differences may explain most of the withdrawals in clinical stages. To illustrate, most mouse models do not develop key neuropathological phenotypes such us neurodegeneration or neuroinflammation.4 In many cases, key proteins and pathways involved in the onset of NDDs are not conserved in rodents5 and the massive overexpression of genes needed to induce a mild symptomatology do not relate to human disease. Moreover, there are substantial differences in metabolism, which directly impacts drug responses.6 Other limitations are expected because of their less-developed brain and shorter lifespan which hampers the study of age-related diseases.4