QurAlis Technology

Optopatch

Communication and processing in the brain is accomplished by electrical signals in neurons. In many neurological disorders, such as epilepsy or schizophrenia but also ALS, the electrical signaling does not work well. Traditionally, scientists have measured these electrical signals by manually piercing individual neurons with a microscopic electrode. The technique, called patch clamp electrophysiology, has revealed much of our understanding of brain function and has been awarded multiple Nobel Prizes, but it is a slow and labor intense process which requires a highly skilled operator. Another disadvantage of the technology is that the cells are pierced with the electrode and the internal and external environment of the cells are modified which changes their behavior. At QurAlis and Q-State Biosciences, we use the Optopatch technology to both stimulate the neurons and record their electrical behavior with light: each neuron emits a brief flash every time it sends an electrical signal. We use our custom microscopes to record from more than 100 neurons in parallel, a recording speed 1000's of times higher than that of manual patch clamp. The throughput of Optopatch enables us to rapidly identify unhealthy electrical signaling in diseased neurons and screen for compounds that correct the aberrant behavior. By using this technology we have found that the anti-epileptic drug retigabine can rescue activity defects that exist in the neurons of ALS patients.

QurAlis has developed a proprietary method to clear toxic DPR proteins. We are now developing a cartridge which will be incorporated in our Clear CSF device. This device will clear the toxic DPR repeat proteins from the CSF of ALS patients that carry the C9orf72 repeat expansion mutation. To recirculate the CSF safely, a sophisticated pumping system is required for which QurAlis is partnering with other companies that have extensive experience in CSF device development. Our final therapy for ALS patients will be a wearable device like an insulin pump that will continuously clear the CSF from toxic proteins to stop them from harming neurons.

Optopatch
Optopatch: All-optical electrophysiology. (a) Optopatch is comprised of the blue light-stimulated channelrhodopsin CheRiff and the red light-emitting voltage sensor QuasAr. Both are membrane proteins that can be transfected into neurons. (b) The current through CheRiff, and thus the stimulus strength, can be tuned with the blue light intensity. (c) The fluorescence of QuasAr is linearly proportional to transmembrane voltage, enabling simple interpretation of fluorescence recordings. (d) When these proteins are expressed in mammalian neurons, they traffic to the cell membrane. In the rat hippocampal neuron here, the tiny tufts on the membrane are individual spines, showing the location of individual synapses. (e) QuasAr fluorescence tracks beautifully with gold-standard patch-clamp voltage recordings. Action potentials are triggered with high fidelity with blue light.

Stem Cell Research

Stem Cell Technology

Thanks to the discoveries of Dr. Yamanaka in 2006 we can now take blood or skin cells from living ALS patients and reprogram these into stem cells. These stem cells can then be used to make the motor neurons that are dying in ALS patients. These motor neurons carry the same DNA and gene mutations as the ALS patients and can be used to study the disease in laboratory. Through these stem cell models, the research community has identified a lot of things that go wrong in the cells of ALS patients. These discoveries can be used to discover and develop new medicines for ALS patients. This is exactly what QurAlis is doing and what were a really good at. Also, we hope that through these stem cell models we will be able to identify the cause of the disease for the large group of ALS patients for which we have not been able to identify any ALS genes yet.

Clearance of Toxic Proteins from the CSF

Toxic proteins are generated in ALS and FTD patients with C9orf72 mutations. These proteins travel through the brain and spinal fluids and are taken up by neurons of the motor system that are very sensitive to their toxicity which leads to degeneration of these neurons leading to paralysis. QurAlis has developed a proprietary technology which safely clears these toxic proteins from the brain and spinal fluids of C9orf72 ALS and FTD patients. We are now developing this technology into a device that will safely recirculate the brain and spinal fluids while the toxic proteins are rendered harmless. With this technology QurAlis aims to stop or significantly slow down the neuronal degeneration in ALS and FTD patients with C9orf72 mutations. This technology can potentially be used for other forms of ALS and FTD in which toxic prion like proteins propagate through the brain and spinal fluids.

Clearance of Toxic Proteins from the CSF

Smith, R., et al., Amyotrophic lateral sclerosis: Is the spinal fluid pathway involved in seeding and spread? Med Hypotheses, 2015. 85(5): p. 576-83.

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