| Autor: |
Skov, Martin, Ruijs, Titia Q., Grønnebæk, Thomas S., Skals, Marianne, Riisager, Anders, Winther, Jeppe Blichfeldt, Dybdahl, Kamilla Løhde Tordrup, Findsen, Anders, Morgen, Jeanette J., Huus, Nete, Broch-Lips, Martin, Nielsen, Ole B., de Cuba, Catherine M.K.E., Heuberger, Jules A.A.C., de Kam, Marieke L., Tannemaat, Martijn, Verschuuren, Jan J. G. M., Knutsen, Lars J. S., Kelly, Nicholas M., Jensen, Klaus G. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 3/20/2024, Vol. 16 Issue 739, p1-15, 15p |
| Abstrakt: |
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl−) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670. Editor's summary: Myasthenia gravis (MG) is caused by an autoimmune response against postsynaptic components of the neuromuscular junction, leading to impaired communication between motor neurons and muscle fibers. Here, Skov et al. show that inhibition of the ClC-1 chloride channel with an orally bioavailable small molecule (NMD670) augmented muscle excitability in response to motor commands and thereby improved muscle function in rat models of MG. Data from a small randomized clinical trial demonstrate that treatment with NMD670 was well tolerated in patients with MG and improved a quantitative disease severity score. These findings support further clinical development of ClC-1 inhibitors for MG. —Daniela Neuhofer [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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