Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates.
J Neuromuscul Dis
; 3(3): 381-393, 2016 08 30.
Article
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| MEDLINE
| ID: mdl-27854228
ABSTRACT
BACKGROUND:
Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD).OBJECTIVE:
Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here.METHODS:
PMOs were administered once-weekly by bolus intravenous (IV) injections to male NHPs. Endpoints evaluated included plasma exposures, clinical observations, body weight/food consumption, eye exams, electrocardiograms, male reproductive hormones/endpoints, complement alternative pathway, clinical pathology, urinalysis, and macroscopic/light microscopic pathology.RESULTS:
Findings in these studies were limited to the kidneys, with a common presentation of tubular basophilia, vacuolation, and/or minimal degeneration that was considered non-adverse. No necrosis, glomerular lesions, or effects on renal function tests such as serum creatinine or urea nitrogen were observed, suggesting that PMO-related kidney findings are not likely to develop into frank nephrotoxicity. There were no adverse effects on other potential target organs after repeated IV injections at the highest dose levels tested, 320âmg/kg.CONCLUSIONS:
Nonclinical results in NHPs for these three PMOs, together with the excellent clinical safety established for eteplirsen to date, suggest that once-weekly IV administration of PMOs for lifetime durations at therapeutic doses will be well tolerated by patients with DMD.Palabras clave
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Distrofia Muscular de Duchenne
/
Morfolinos
/
Riñón
Límite:
Animals
Idioma:
En
Revista:
J Neuromuscul Dis
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos