Drug repurposing: ALS gets keymaster and gatekeeper tech to delay progression

Neurons communicate with each other through synaptic transmission, which involves both the release of chemical neurotransmitters and electrical activity. This communication can be either excitatory or inhibitory. Excitation is like the gas pedal in your car and inhibition is the brake pedal. Too much gas and you’ll speed off the road; too much brake and you don’t go anywhere. In a healthy brain, a balance between excitation and inhibition ensures proper brain function — enabling us to solve math problems, retrieve memories and feel emotion. But too much excitation in the brain’s neurons can lead to neurological disorders like epilepsy, neuropathic pain, autism spectrum disorders, schizophrenia and ALS. Commonly known as Lou Gehrig’s disease, ALS is caused by the degeneration and loss of neurons that control muscles. There is no cure for ALS which currently affects none less than 100.000 people around the world. In Canada, the current number of affected subjects is estimated between 2000 and 3000.

Now, a team of researchers led by scientists at the University of Toronto has claimed to have delayed the onset of ALS in mice. The result was achieved in mice that possessed the same gene mutation (SOD1) found in some human ALS patients. The researchers targeted neurons in the motor cortex — the region of the brain that controls muscles — with an engineered protein designed to correct an imbalance in neurons referred to as hyperexcitability. While human SOD1 gene mutation carriers display pronounced cortical hyperexcitability in the decade prior to the onset of ALS, it wasn’t clear it was a cause of neuronal degeneration. Scientists knew before that there was a very profound imbalance between excitation and inhibition in the region of the brain that controls movement. But that didn’t tell them whether this hyperexcitability caused the onset of symptoms. Now they know that in ALS mice with the SOD1 mutation, hyperexcitability in the motor cortex is causal to the onset of the disease.

Melanie Woodin, professor in the Department of Cell & Systems Biology and a co-author of a study published recently in the journal Brain, and her colleagues are combining advances in viral technology with a revolutionary technique in neuroscience called chemogenetics. Proteins that had their structure altered were introduced into mice via a virus and delivered to neurons in the primary motor cortex. Once there, they were activated with a pharmaceutical drug — but one which isn’t approved for use in humans. However, other scientists demonstrated that a drug called clozapine, which is approved for use in humans for the treatment of certain psychiatric disorders, could also activate the protein. And while chemogenetics was employed in the current study, it isn’t currently used in human patients in part because of the challenge in delivering the chemogenetic “tool” to the right neurons. But two scientists in her lab are testing a non-invasive procedure to deliver therapeutic agents to the motor cortex of ALS patients.

Normally the brain is protected by a natural barrier (BBB) that keeps out pathogens like bacteria and viruses — but that also keeps out therapeutics like drugs and proteins. With the new technique, the blood brain barrier can be temporarily and safely opened to deliver a protein to targeted regions of the brain. Dr. Wooden explained: “Our experiment profoundly delayed the disease by preventing the degeneration of neurons in the cortex of the brain. It delayed typical symptoms of ALS like the deterioration of motor skills and weight loss. It also increased the survival rate. The result is important because it points down a path for a potential treatment in humans. The optimism that the result could eventually lead to a treatment in humans is bolstered by the fact that it comprises advances which have yet to be used together but that are proven on their own. The clozapine discovery was a game-changer for our work. It revealed a clear path for clinical translation which just wasn’t there when we first developed our hypothesis”.

Dr. David Taylor, vice president of research at ALS Canada, is aware if the results and released a statement: “Despite the fact that both upper motor neurons in the cortex and lower motor neurons in the body are degenerating in ALS, much of the research to date has ignored the role of upper motor neurons. Excessive activity of the upper motor neurons could be an important contributor to the disease and Professor Woodin’s work focused on a novel way to stimulate neighbouring neurons, that can put the brakes on this abnormal biology. Her results in ALS model mice are exciting and hopefully this can someday be a treatment strategy tested in human clinical trials”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Khademullah CS et al. Brain. 2020; 143(3):800-810. 

Salmon CK et al. Front Cell Neurosci. 2020 Feb; 14:36. 

Mahadevan V et al., Woodin MA. Elife 2017; 6:e28270.

Pressey JC et al. J Biol Chem. 2017; 292(15):6190-201. 

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Informazioni su Dott. Gianfrancesco Cormaci 2450 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it
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