In 1934, Mary Walker, a pioneering Scottish physician, successfully, albeit transiently, treated a myasthenia gravis patient with physostigmine, a traditional remedy for treating poisoning with curare. She had noticed that the signs and symptoms of myasthenia gravis resembled those caused by curare, a preparation of plant alkaloids used to arm poison arrows by some indigenous peoples in Central and South America. Her clinical observations were extraordinarily accurate. At a molecular level, curare, which induces muscle paralysis, acts as a competitive inhibitor of the neurotransmitter acetylcholine by binding the nicotinic acetylcholine receptor and preventing the transmission of an action potential across the neuromuscular synapse, which would ordinarily lead to muscle contraction.

In myasthenia gravis a similar problem arises due to the presence of autoantibodies that bind to and block the nicotinic acetylcholine receptors expressed on muscle cells. (In a minority of patients, the auto-antibodies may bind to other proteins present in the neuromuscular junction, such as muscle-specific kinase or LPR4). The condition, which literally means ‘serious muscle weakness’, is highly variable. The muscles affected include those involved in controlling the movement of the eyes and eyelids, facial expression, chewing, speaking, and swallowing. Additional damage to the neuromuscular synapse develops through the activation of the complement system. Although most people who have the condition have a normal life expectancy, a minority experiences life-threatening crises, when the muscles that control breathing cannot function. They require ventilator assistance and therapeutic interventions, such as plasma exchange or intravenous immunoglobulin.

Walker’s remedy, physostigmine, a natural product isolated from a number of tropical plant species, was an early example of a cholinesterase inhibitor, which boosts levels of endogenous acetylcholine by slowing its breakdown. Cholinesterase inhibitors remain a mainstay of therapy along with immunosuppressive therapies and surgical removal of the thymus, which remains active in some patients, and which may contribute to their immune dysfunction. In more recent years, antibody-based therapies that target either complement activation or the neonatal Fc receptor (which maintains IgG antibodies, including autoantibodies, in circulation) have come to the fore. CAR-T cell therapies are also in the mix, although the data here are so far mixed. But the long tradition of innovation in treating myasthenia gravis continues.

Companies mentioned in this episode:
Ablynx, Alexion, Argenx, AstraZeneca, Cartesian Therapeutics, Harbor Biomed, Johnson & Johnson, Kyverna Therapeutics, NMD Pharma A/S, UCB

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