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hPSC & drug discovery

hPSC & drug discovery

Pluripotent stem cells and drug discovery: the march to the clinic.


In his 2008 Cell essay, “Stem cells and drug discovery: The beginning of a new era?” Lee Rubin1 expressed the hope held by many researchers that human pluripotent stem cells (PSC: hESC and hiPSC) and their derivatives would revolutionize drug discovery. Many held that emerging, PSC-derived models of human diseases would substitute for or complement the use of animal disease models, and in the process, also provide assays for potential drug toxicity and front line screens for therapeutic candidates.  Do developments over the past nine years justify the initial optimism?


There is no doubt that during this period, PSC research has seen enormous progress.  There has been an exponential rise in the number of papers reporting new PSC-based disease models, and a significant increase in the range of cell types that can be differentiated in vitro. These models have often provided unique insights into disease pathology and when fueled by robust, scalable differentiation protocols [Genea Biocells’ skeletal muscle production being a case in point2], can facilitate drug screening and toxicity programs. But has any of this progress expedited the emergence of drugs for hitherto intractable congenital conditions?  The answer is a resounding “yes.”  There are currently at least three drugs where stem cell modeling played a pivotal role in their identification, now in clinical trials. These drugs are a monoclonal antibody (sponsored by Bristol Myers Squibb) targeting a condition known as progressive supra-nuclear palsy, and two small molecules, one (sponsored by Roche) targeting SMA and the other (sponsored by GlaxoSmithKline) targeting ALS 3,4 .


The monoclonal antibody (BMS-986168) was developed after Bright and colleagues found that cortical neurons made from hiPSC generated from an Alzheimer’s patient, secreted extracellular tau molecules into the surrounding culture medium. The therapeutic impact of the antibody is thought to be mediated by its ability to prevent tau aggregation.


Meanwhile, Naryshkin and colleagues made iPSC-derived motor neuron from SMA patients and used them to screen for compounds that could rescue the disease phenotype.  “Hits” were further validated using mouse models of SMA and one of these (RG7800) is now in clinical trials.  


Woolf and colleagues were studying the phenotype of iPSC-derived motor neurons made from an ALS patient with an SOD1 mutation.  They found that such neurons displayed an intrinsic membrane hyper-excitability which could be eliminated either by correction of the mutation or by treating cells with retigabine (also called ezogabine).  Their choice of retigabine was guided by their knowledge that this drug had been approved for clinical use as an anticonvulsant in epilepsy where its ability to activate potassium channels reduced neuronal hyper-excitability.  This drug is now in trials for ALS ( the manufacturer has recently discontinued its use for epilepsy on commercial grounds).  This last example involved the repurposing of an approved drug for a new indication-this route to the clinic is very attractive to companies because many of the safety issues involved in that drug’s use will have already been covered in previous clinical trials.  


Genea Biocells creates human pluripotent stem cell derived skeletal muscle for drug discovery.


Genea Biocells is currently focusing most of its drug discovery efforts on SMA and FSHD. For the latter indication, there are NO suitable animal models that can be used for proof-of-concept studies. Genea Biocells’ PSC-derived skeletal muscle models are ideal for drug screening and evaluation and the use of those model systems has already significantly advanced Genea Biocells’ drug development programs.


Glossary:  ALS, amyotrophic lateral sclerosis FSHD, facioscapulohumeral dystrophy; SMA, spinal muscular atrophy; SOD, superoxide dismutase



  1. Rubin, L.L. (2008). Stem Cells and Drug Discovery: The Beginning of a New Era? Cell,132(4), 549-552.
  2. Caron, L., et al. (2016). A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles. Stem Cells Translational Medicine, 5(9), 1145-1161.
  3. Shi, Y., et al. (2017). Induced Pluripotent Stem Cell Technology: A Decade of Progress. Nature Reviews Drug Discovery, 16,
    115-130. doi: 10.1038/nrd.2016.245
  4. Wainger, B., et al.(2104). Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons. Cell Reports, 7(1) 1-11.


Alan Colman 12 Oct 2017


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