ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Invest 2017;127:3861-3865

Metaphyseal chondrodysplasia, Schmid type (MCDS) is an orphan disease with highly abnormal endochondral ossification causing shortening and deformities of the limbs, impairment of mobility and chronic pain. As for most skeletal dysplasias, current treatment options remain symptomatic due to the lack in causal therapeutic measures. In the actual study the authors took advantage of the well-described pathogenesis in MCDS: In contrast to other collagenopathies, collagen X mutations do not directly lead to structural deficits but induce ER-stress by accumulation of misfolded protein. The authors hypothesize that by pharmacologically upregulating autophagy, enhanced protein clearance would ameliorate ER-stress and improve associated pro-apoptotic and differentiation-inhibiting effects.

Using a testing battery of known effectors of ER-stress and protein degradation, Mullan et al. identified carbamazepine (CBZ, Tegretol®) as sole active compound regarding MCDS-specific cellular characteristics. Carbamazepine has been shown to induce both autophagy by cellular depletion of myo-inositol and proteasome activity by unknown mechanisms (1, 2). The authors could show both in vitro and in vivo an ameliorated chondrocyte phenotype and improved linear growth in mice. Interestingly, the drug was able to stimulate misfolded protein degradation by both autophagy and by proteasomal pathways, thus being effective for mutations being dependent on either pathway.

Given the positive safety profile of CBZ in pediatric patients, this study impressively resulted in an EMEA orphan drug license for the use CBZ in MCDS. Thus, the work of Mullan et al. did not only result in a new therapeutic option in MCDS but may also give hope for further rare diseases benefitting from repurposing well-established drugs.

1. Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, Klapholz C, Coulter S, Obregón-Henao A, Henao Tamayo M, Basaraba R, Kampmann B, Henry KM, Burgon J, Renshaw SA, Fleming A, Kay RR, Anderson KE, Hawkins PT, Ordway DJ, Rubinsztein DC, Floto RA. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med. 2015;7(2):127-39.

2. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010;329(5988):229-32.