The effect of hydroxyurea in spinal muscular atrophy cells and patients.
BACKGROUND
Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients.


METHODS
Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated.


RESULTS
After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup.


CONCLUSIONS
Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebo-controlled, double-blind trials are needed to further investigate its efficacy.
Liang
Wen-Chen
WC
Department of Pediatrics, Kaohsiung Medical University Hospital, Taiwan.
Yuo
Chung-Yee
CY
Chang
Jan-Gowth
JG
Chen
Yi-Ching
YC
Chang
Yung-Fu
YF
Wang
Hui-Yi
HY
Ju
Yun-Huei
YH
Chiou
Shyh-Shin
SS
Jong
Yuh-Jyh
YJ
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D018737:Hand Strength; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D015999:Multivariate Analysis; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
D017362:Cyclic AMP Response Element-Binding Protein; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009419:Nerve Tissue Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D006918:Hydroxyurea