TY - JOUR
T1 - The dcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models
AU - Gogliotti, Rocky G.
AU - Cardona, Herminio
AU - Jasbir, Singh
AU - Bail, Sophie
AU - Emery, Carina
AU - Kuntz, Nancy
AU - Jorgensen, Michael
AU - Durens Madel, M.
AU - Xia, Bing
AU - Barlow, Courtenay
AU - Heier, Christopher R.
AU - Plasterer, Heather L.
AU - Jacques, Vincent
AU - Kiledjian, Megerditch
AU - Jarecki, Jill
AU - Rusche, James
AU - Didonato, Christine J.
N1 - Funding Information:
This work was supported by funding from the Families of SMA and Repligen Corporation. Repligen Corporation received funding from the Muscular Dystrophy Association. In addition, C.J.D. was supported by National Institutes of Health (1RO1NS060926-04 and 5R21 NS067482-02) and M.K. was supported by the Families of SMA. C.E. and R.G.G. were supported by the National Institutes of Health training grants (5T32GM008061) and (T32 AG000260), respectively. Families of SMA financially supported and directed the identification and generation of the quinazoline series of compounds, including RG3039.
PY - 2013/10
Y1 - 2013/10
N2 - Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to thefunctional lossof theSMN1geneandtheinabilityof itsparalog,SMN2, tofullycompensateduetoreducedexon 7 splicing efficiency. SinceSMA patients have at least one copy ofSMN2, drug discovery campaigns have sought to identifySMN2inducers.C5-substituted quinazolines increaseSMN2promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varyingdiseaseseverity (Taiwanese 5058Hemiand2B/2SMAmice), andpositively impact sneuromuscular pathologies. In 2B/2 SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosingbegan atP4, highlightingthe importanceof early intervention.We determinedthe minimumeffective dose and the associated pharmacokinetic (PK) and exposure relationship ofRG3039 and DcpS inhibition ex vivo. These data support the long PKhalf-life with extended pharmacodynamic outcome of RG3039 in 2B/2 SMA mice. Inmotorneurons,RG 3039 significantly increased both theaverage number of cell swithgemsandaveragenumber of gems per cell, which is used as an indirectmeasure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
AB - Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to thefunctional lossof theSMN1geneandtheinabilityof itsparalog,SMN2, tofullycompensateduetoreducedexon 7 splicing efficiency. SinceSMA patients have at least one copy ofSMN2, drug discovery campaigns have sought to identifySMN2inducers.C5-substituted quinazolines increaseSMN2promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varyingdiseaseseverity (Taiwanese 5058Hemiand2B/2SMAmice), andpositively impact sneuromuscular pathologies. In 2B/2 SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosingbegan atP4, highlightingthe importanceof early intervention.We determinedthe minimumeffective dose and the associated pharmacokinetic (PK) and exposure relationship ofRG3039 and DcpS inhibition ex vivo. These data support the long PKhalf-life with extended pharmacodynamic outcome of RG3039 in 2B/2 SMA mice. Inmotorneurons,RG 3039 significantly increased both theaverage number of cell swithgemsandaveragenumber of gems per cell, which is used as an indirectmeasure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
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U2 - 10.1093/hmg/ddt258
DO - 10.1093/hmg/ddt258
M3 - Article
C2 - 23736298
AN - SCOPUS:84881560530
SN - 0964-6906
VL - 22
SP - 4084
EP - 4101
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 20
M1 - ddt258
ER -