Human Amyotrophic Lateral Sclerosis iPSC Model

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Amyotrophic lateral sclerosis, ALS, also called „Lou Gehrig's Disease,“ is a fatal, late-onset disease with severe diagnosis and not cure today. ALS targets motor neurons and causes their loss and eventually causes loss of motor function muscle movement. ALS occurs as a bulbar or spinal ALS.

NeuroProof is a drug screening company offering new functional phenotypic screening assays for new potential disease-modifying treatments of ALS.

ALS is a rare disease with no clear etiology. 10% of patients have a familial hereditary form of ALS, familial ALS, fALS, but most of the patients, 90%, suffer on sporadic ALS. Sporadic and familial forms are clinical identical.

Examples of Familial Forms of Amyotrophic Lateral Sclerosis

Familial ALS is caused by mutations as SOD1, TDP43, FUS, C9ORF72, and others.The mutations SOD1 are mutations of the enzyme Cu/Zn-superoxide dismutase 1. These mutations cause degeneration of motor neurons by oxidative stress, protein aggregates, mitochondrial defects, and glutamate excitotoxicity.

The TAR DNA-binding protein 43 (TDP-43) is another mutation that causes fALS. The misfolded protein TDP43 contributes to motor neuron's death. It is supposed that SOD1 mutation and misfolding of TDP43 are related.

The C9ORF72 gene is implicated in ALS of a repetition of GGGGCCG expansion in non-coding regions with effects on RNA binding and autophagy regulation.

Neurodegenerative mechanisms in ALS are very diverse, which explains the difficulties to develop new treatments for this disease.

NeuroProof's iPSC Derived Motor Neuron Superoxide Dismutase 1 Model

NeuroProof uses human motor neurons from a human induced pluripotent stem, iPSC, cell line with a SOD1 mutation D90A, and its isogenic corrected control. These iPSC derived motoneurons are cultivated on microelectrode arrays, MEA, and form spontaneous active neuronal cultures. With this, NeuroProof test compounds in a functional phenotypic disease model of ALS.
A disturbed excitatory-inhibitory balance, E/I balance, characterizes ALS SOD1 mutated motor neurons activity. In particular, iPSC derived motoneuron cultures with a SOD1 mutation show a hyper-excitation in comparison to their isogenic control.

Description of An Example with a SOD1-D90A  mutation ALS Rescue Assay

We used an ALS-patient cell line carrying a SOD1-D90A mutation and its isogenic control differentiated in motor neurons. We recorded spike train data at day 11 in vitro, see here.

ALS SOD1 D90A Spike Train Parameter

Image:Spike train parameter comparison of a SOD1-D90A cell line and its isogenic control, demonstrating a highly hyper-excited activity pattern of the ALS mutated cell line.

These cell lines are used for a rescue assay. With a specific projection of the spike train parameters into a one-dimensional effect-score, it is possible to assess the putative therapeutic effect of a compound.

tl_files/media/img/Services/ALS SOD1 D90A Effect Score.png

Image:Example of a compound's effect in an ALS rescue assay. It is assessed the reversion of a compound from the diseased cell line normalized at one to the healthy cell line normalized at zero.


NeuroProof offers screening services with its unique screening technology for a wide range of diseases.

NeuroProof is continuously expanding its assay portfolio, ask us for potential new ALS cell lines with familial or sporadic forms. NeuroProof performs integrated project from sourcing of diseased cell lines, cell differentiation, assay development to compound screening campaigns.


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