Engineered agrin attenuates the severity of experimental autoimmune myasthenia gravis

Abstract

We demonstrated that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. Muscle Nerve 57: 814-820, 2018.

Dissecting the Extracellular Complexity of Neuromuscular Junction Organizers

“…Thus, regulation of agrin proteolysis offers an interesting therapeutic prospective for pathologies associated to neuromuscular degeneration. Modulation of NT activity, as well as agrin-derived therapeutics, could provide a means to delay or compensate the progression of the pathology at a NMJ level, and provide a retrograde positive signal counteracting, in part, the associated motor neuron loss (Hettwer et al, 2014;Boido et al, 2018;Li Z. et al, 2018).…”

“…In light of these observations, alternative therapeutic approaches are a necessity. One possibility takes into consideration the use of recombinant agrin constructs incorporating the C-terminal region of neural (z+) agrin known to induce AChR clustering (Hettwer et al, 2014;Li Z. et al, 2018). Specifically, a soluble C-terminal agrin fragment (NT1654) (Hettwer et al, 2014) spanning the domains.…”

“…Specifically, a soluble C-terminal agrin fragment (NT1654) (Hettwer et al, 2014) spanning the domains. This recombinant protein, engineered to resist NT cleavage, was seen to hold significant potential in stabilizing NMJ's and alleviating autoimmune MG (Li Z. et al, 2018). Interestingly, agrin's possible therapeutic applications seem to extend beyond myasthenic syndromes to other pathologies associated with muscle degeneration.…”

Spinal muscular atrophy counteracted by Agrin biological NT-1654

“…In short Agrin aids to delay the SMA progression, and therefore it can be identi ied as an effective compound (NT-1654) that could be potentially tested in human trials. As NT-1654 does not induce immune response, nor anti-Agrin antibody production it can be considered safe [12]. Agrin represent a good strategy to prevent muscle atrophy and decelerating the pathological cascade affecting MNs and NMJs in this way allowing a more extended therapeutic window.…”

“…The administration of NT-1654 to SMA can compensate for the reduction of Agrin. In combination with anti-apoptosis treatment, provided boon in the disease progression in congenital muscular dystrophy, stimulating stabilization of muscle ibers, muscle growth/strength and regeneration [12].…”