HoldsUp

Paul Fernyhough

Paul Fernyhough is a researcher in the field of neuroscience with a focus on peripheral nerve disorders. His published research investigates mechanisms and treatments for diabetic peripheral neuropathy, mitochondrial dysfunction, and neuritogenesis. In particular, his work explores the therapeutic potential of muscarinic acetylcholine receptor antagonists to stimulate axonal repair and neurite outgrowth in sensory neurons.

8 claims checked on air: 7 supported 1 unverified

What they said on air - supported

3 citing their own research

0:00:00supportedvery lowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Targeting mitochondria to increase their function can overcome the neurodegenerative process in peripheral neuropathy.

"if you target the mitochondria to drive up its function, you can overcome the degenerative process." (said at 0:00:00)

Preclinical models of peripheral neuropathy (such as diabetic, chemotherapy-induced, and HIV-associated neuropathies) demonstrate that enhancing mitochondrial bioenergetics and calcium homeostasis (e.g., via muscarinic receptor antagonism or TRPM3 activation) can promote axonal repair and overcome neurodegenerative phenotypes. However, while these strategies show promising disease-modifying potential in cellular and animal models, evidence in human clinical trials remains preliminary.

0:15:33supportedhighExciting Developments in the Treatment of Peripheral Neuropa

Certain HIV therapeutics impair mitochondrial function.

"some of the HIV therapeutics actually hit mitochondrial function, which is one of our targets with our drug that we'll hear about later." (said at 0:15:33)

It is well-established that certain antiretroviral therapeutics, particularly nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine, stavudine, and didanosine, impair mitochondrial function. The classical mechanism involves the inhibition of human mitochondrial DNA polymerase-gamma (Pol-γ), leading to mitochondrial DNA depletion, respiratory chain dysfunction, and clinical complications such as peripheral neuropathy, myopathy, lipoatrophy, and lactic acidosis.

0:17:35supportedmoderateExciting Developments in the Treatment of Peripheral Neuropa

Unmyelinated nerve fibers require local ATP production along their entire length for conduction, whereas myelinated fibers produce ATP primarily at the nodes of Ranvier.

"many of them you have unmyelinated fibers, which means the nerve conduction has to go all the way along the nerve with local production of ATP along the whole length of the nerve as opposed to a myelinated nerve where you have energy production primarily at the nodes of Ranvier." (said at 0:17:35)

The speaker's statement accurately reflects basic axonal physiology and bioenergetics. In unmyelinated axons, continuous impulse propagation requires ion pumping (Na+/K+-ATPase) and ATP production uniformly distributed along the entire length of the fiber. In contrast, myelinated axons employ saltatory conduction, confining action potential regeneration and the highest metabolic demands primarily to the unmyelinated gaps (nodes of Ranvier), where axonal mitochondria are preferentially clustered.

0:18:25supportedlowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Excess glucose entering neurons shifts their metabolism toward glycolysis, leading to downregulation and loss of mitochondria.

"Its metabolism is affected by all this sugar that's coming into the neuron. And as a result, it becomes more reliant upon glycolysis. And so, it actually switches off its mitochondria as almost as an inbuilt system. And what this means though in terms of neurons, especially the nerve endings, which have very high energy requirements, you actually see a loss of mitochondria, and it's been shown in human tissue as well as animal studies." (said at 0:18:25)

Nutrient excess and elevated intracellular glucose concentrations in sensory neurons trigger metabolic maladaptation via nutrient-sensing pathways (such as AMPK/SIRT/PGC-1α), causing suppression of mitochondrial oxidative phosphorylation and a shift toward glycolysis. This downregulation of mitochondrial respiratory chain gene expression, function, and distal energetic capacity in energy-demanding nerve endings has been demonstrated in both animal models of diabetes and human tissue biopsies.

0:32:45supportedhighExciting Developments in the Treatment of Peripheral Neuropa

There are five distinct subtypes of muscarinic acetylcholine receptors.

"It's relatively specific for a G protein coupled receptor called the muscarinic receptor. It's actually a type 1. There's actually five subtypes, so it's quite complex." (said at 0:32:45)

The claim is supported by established pharmacological and molecular biology literature. Muscarinic acetylcholine receptors are a family of five distinct G protein-coupled receptor subtypes designated M1 through M5.

0:34:05supportedvery lowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Acetylcholine binding to the muscarinic receptor sends a negative signal that inhibits sensory neuron growth, and blocking this receptor with an antagonist removes this cholinergic constraint and increases nerve growth.

"what we've discovered is that the muscarinic receptor is a key component of a negative influence. So acetylcholine, which is a neurotransmitter, binds to the muscarinic receptor, sends a negative signal that inhibits growth. And we've done lots of studies to uncover all that. And so, when you come in with an antagonist or a blocker of the receptor, you block this cholinergic constraint, as we as we termed it, and you see increased growth." (said at 0:34:05)

Preclinical in vitro and animal studies demonstrate that endogenous acetylcholine acts via muscarinic acetylcholine type 1 receptors (M1R) to exert a tonic inhibitory effect ('cholinergic constraint') on adult sensory neuron neurite outgrowth and mitochondrial function. Genetic knockout of M1R or pharmacological blockade using selective M1R antagonists (such as pirenzepine or MT7) removes this inhibition and promotes sensory neuron growth and peripheral nerve regeneration.

0:34:45supportedhighExciting Developments in the Treatment of Peripheral Neuropa

Approximately 35% of all FDA-approved drugs (around 700 drugs) interact with G-protein coupled receptors (GPCRs).

"There are 700 FDA-approved drugs that interact with GPCRs. I think it's like 35% of all drugs involve GPCRs, and that's what our drug is doing." (said at 0:34:45)

Published pharmacological analyses and reviews of FDA databases confirm that approximately 34% to 35% of approved drugs target G protein-coupled receptors (GPCRs). Depending on how individual drug entities, salt forms, and combinations are counted across databases (such as ChEMBL, Guide to PHARMACOLOGY, and the FDA Orange Book), estimates of the total number of approved GPCR-targeting drugs range from roughly 475 to approximately 700.

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