September is Alzheimer’s awareness month. Alzheimer’s disease (AD) is affecting a big part of the elder population worldwide but there is no cure yet. We interviewed Laura Calo, PhD, to find out more about AD research and the role of human induced pluripotent stem cells (hiPSC) in discovering new drugs for AD and other neurodegenerative diseases. Dr. Calo is a senior neuroscientist at Ncardia and has a long expertise in the generation of iPSC models for neurodegeneration.
Q: According to you, what are the reasons that a cure for AD has not yet been found?
A: Developing new therapies for neurodegenerative diseases is a long process and the attrition rate is relatively high, compared to other therapeutic areas. The main reasons are the complex pathological mechanisms and the lack of translational models. Traditionally, primary neurons from rodents and non-neuronal human cell lines were used for AD research, which cannot fully recapitulate the pathology of AD. When working with in vivo animal models, translational capabilities are limited because of the animals’ short lifespan and differences in protein function and cell-cell interactions. hiPSC-derived AD models can play an essential role in overcoming these limitations.
Furthermore, many drug discovery campaigns have been focusing on drugs that reduce the formation of amyloid-β plaques in the extracellular space, which is one of the pathological features of AD. Several drugs targeting the formation of these plaques reached clinical trials but failed to significantly rescue the cognitive decline in AD patients. Recently, more studies are focusing on other aggregation-prone proteins such as the microtubule associated protein TAU, and on the role of non-neuronal populations such as microglia and astrocytes in AD.
Traditional models have limited translational capabilities. The increasing understanding of AD etiology and hiPSC technology is helping to overcome the limitations
Q: What is needed to generate an Alzheimer’s disease model using hiPSCs?
A: I think the most important thing is to have a good knowledge of cell biology and understanding of Alzheimer’s pathophysiology. When creating a disease model, first, somatic cells from AD patients or healthy donors are reprogrammed and differentiated into the major brain cell types. Certain mutations or culture conditions will then help to model AD in vitro and different assays are performed to validate the model. The combined expertise in sourcing, reprogramming and manufacturing hiPSCs that we have at Ncardia, is really facilitating all the steps to generate hiPSC-derived disease models. For me, it is so interesting how we are developing co-culture models of hiPSC-derived astrocytes or microglia together with neurons which provide a more physiologically relevant context for the study of neurological diseases.
Q: How can hiPSC-derived Alzheimer’s disease models effectively be used for drug discovery?
Ncyte CNS culture. TH (red), βIII-Tubulin (Green) & DAPI (blue)
The incorporation of hiPSC-derived AD models into the early phases of drug discovery brings many benefits. They provide a human cellular context that can help select the most effective and safe compounds, decreasing the high attrition rate of drugs developed in non-human cellular systems. The influence of aging in AD can be recapitulated with hiPSC-derived models. Many AD-related changes in neural activity occur early in the aging process, such as altered cellular electrophysiology, impairment of autophagy and mitochondrial dynamics or reduction of synaptic proteins expression. In order to identify compounds that slow or halt pathology progression, it is key to develop sensitive assays for the evaluation of those early changes. As a scientist working at Ncardia, I really appreciate the broadness of our capabilities, and the flexibility that we have to design custom projects and assays at high throughput level.
Ncardia facilitates all the steps to generate hiPSC-derived disease models and brings hiPSC technology to the early phases of drug discovery
Q: How do you see the future of hiPSC for Alzheimer’s disease research, what will be possible?
A: Technology and protocols are evolving rapidly, and processes are becoming more and more efficient. Scientists are currently working to improve differentiation protocols to enrich for specific neuronal sub-populations, to be able to identify which cells are most vulnerable to a particular stress or drug. I think the next opportunity would be to employ hiPSC-derived AD models in target-agnostic high throughput screenings, which will help identifying novel pathways involved in AD pathophysiology. I am convinced that hiPSCs have an essential role in understanding and ultimately finding a treatment for Alzheimer’s disease, and that this technology will help bring better therapies to Alzheimer’s patients faster.
The next opportunity would be to employ hiPSC-derived AD models in target- agnostic high throughput screenings