Patient-derived Cell Model for Use in ALS Research Wins International 3Rs Prize

Ana Pena, PhD avatar

by Ana Pena, PhD |

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A model of motor neuron disease based on patient-derived stem cells won the 2018 International 3Rs Prize for its potential to lessen or replace the use of animals as models in amyotrophic lateral sclerosis (ALS) research.

The prize, given by the National Center for the 3Rs (NC3Rs) and sponsored by GlaxoSmithKline (GSK), awards a total £30,000 (currently, almost $40,000) each year to outstanding and original scientific work that has or could have major impacts on 3Rs policy — replacement, reduction or refinement — of living animals being used in research.

Its intent is to promote more humane research, reducing the numbers of animals needed and improving their welfare.

This year’s award went to the lab of Rickie Patani, PhD, MRCP, for the study “Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS” published in Cell Reports in 2017.

Patani is a group leader at the Francis Crick Institute and professor at UCL Queen Square Institute of Neurology. His lab joined efforts with researchers at seven other institutions to develop this project.

This team used induced pluripotent stem cells (iPSCs) collected from ALS patients to derive spinal cord motor neurons and astrocytes (cells important for support, nutrition and repair) in the lab. Both cell types are well-established players in ALS.

Those cells were used to track the sequence of events by which motor neurons degenerate in a genetic form of ALS caused by VCP gene mutations.

Cell imaging and gene activity analysis showed that these lab-derived cells maintain key features of ALS, including cellular stress responses and problems in the formation of motor neuron synapses, the neuron-to-neuron connections that are necessary for nerve signals to be transmitted. Misplacement of a protein called TDP-43 is a hallmark of ALS, and these cells allowed to it be seen an early event — one preceding motor neuron death.

By culturing together motor neurons and astrocytes, the researchers also demonstrated that astrocytes play an important part in ALS, as VCP mutations perturb astrocytes’ ability to support motor neuron survival.

“We have known for some time that iPSCs could be disruptive in biomedical research. This excellent paper demonstrates how this reality is now being achieved not only with potential benefits for patients but also for replacing the use of animals in studies that raise serious welfare concerns,” Stephen Holgate, MD, CBE, chairman of NC3Rs’ board and prize panel, said in a news release.

These ALS iPSCs have a number of scientific benefits over the mouse models, NC3Rs states.

They are able to account for the genetic diversity of patients, investigate sporadic forms of ALS (its most common form), and allow researchers to look at the early molecular events of the disease.

They also provide a new tool for screening potential therapies, and allow some studies to shift from mouse models to cells cultured in the lab. This can have a significant impact for ALS research, as the field has relied heavily on animal models, particularly mice, with around 250 studies a year reporting studies using these models.

Three groups in the UK are already using this new method to replace some of their research in animal models.

“A decade after this work was started, I’m delighted to see that our models are now being widely adopted across several laboratories at UCL Queen Square ION, the Francis Crick Institute and beyond, ” Patani said.

“The overarching vision of my research group is to use these motor neuron and astrocyte models to understand how abnormal RNA transcript structure leads to deregulation of key proteins, and how this in turn causes ALS,” he added.