Celia Dominguez Neurodegenerative Diseases

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.Both this agent along and sodium butyrate showedpromise in a mouse model and in an open-label pilot study, but was not effective ina human Phase II clinical trial [40, 48, 49].Although an increase in the levels of full-length SMN2 mRNA/protein productionis generally regarded as beneficial for the treatment of SMA, there is no consensusregarding its desired magnitude.For example, butyrates and their derivatives fea-tured improved survival of a mouse model of SMA but did not increase SMN levelsin the spinal cord of these mice.On the other hand, fibroblast cultures derived fromSMA patients were treated with therapeutic doses (0.5 500 mM) of VPA to result ina 2- to 4-fold increase in the levels of full-length SMN2 mRNA/protein.VPA wasdiscovered to elevate Smn protein levels through transcription activation in orga-notypic hippocampal brain slices from rats.VPA-treated animals featured both184 A.S.Kiselyov and M.E.Gurneyhigher body weights and significant increase in lifespan.They were able to reorientmore quickly and showed improved limb strength and motor function [50].Sodiumvalproate has induced motor function improvement in patients presumably viaenhancing transcription and reversing SMN2 splicing pattern [51].Hydroxyurea was described to increase the number of gems encapsulatingfunctional Smn protein in cells from Type I to Type IV SMA patients.This agentwas proposed to act via the inclusion of the missing exon from already existingRNA or/and increase in the expression of other transcription factors.Authorsfurther speculated that these events may allow cell to bypass the SMN2 mutation,making it work as a surrogate SMN1 [41, 42].Suberoylanilide hydroxamic acid (SAHA) was introduced as both potent andsafe molecule for the treatment of SMA.SAHA increased Smn protein levels at lowmicromolar concentrations in rat hippocampal brain slices, motoneurone-rich cellfractions, and in a human brain slice culture assay.This agent was more efficientthan VPA in both activating SMN2 and inhibiting HDACs.SAHA also featuresgood oral bioavailability.It was well tolerated and reported to cross the blood brainbarrier [52].A close analog of SAHA, M344 increased full-length SMN2 mRNA,Smn protein level, and number of gems in fibroblast cultures derived from SMApatients.The molecule was noted to be cytotoxic at high concentration featuringtherapeutic index of ca.2 [53].COOHOONaPhenyl butyrate Valproic acidOHNONHOHOH2N NHOHRHydroxyureaSAHA, R = HM344, R = NMe2Trichostatin A, a more potent HDAC inhibitor compared to SAHA, increasedSMN2 expression in cultured cells and in vivo.It ameliorated neuromuscularabnormalities and improved the clinical phenotype of an SMA mouse model [54].Daily treatment of the 5-day-old SMA mice with trichostatin A enhanced the levelof SMN2 expression and production of SMN2 mRNA.In addition, it facilitated theassembly of SMN/RNA complexes.Treatment with trichostatin A restored normalsize to anterior horn cells and increased both total muscle area and myofiberdiameter.Treated mice lived longer and had better motor function.The medianincrease in survival was 3 days (20%).In discussing the mode of action oftrichostatin A, authors suggested that the inhibition of diverse HDACs makesSMN2 (and, perhaps other genes) more accessible to a frequent transcription.However, the main issue associated with HDAC inhibitors is their effect onSpinal Muscular Atrophy: Current Therapeutic Strategies 185off-target genes, especially in the chronic setting.A potential solution may beidentification of the key HDAC enzymes involved in the SMN2 expression andtheir inhibition with highly specific small molecules.Agent TRO19622 featuring steroid template is under development by Trophos.It has successfully completed phase I studies in healthy volunteers and phase Ibstudies in SMA patients.The compound was well tolerated, featured good safetyprofile and PK suitable for once-daily oral dosing based on preclinical models.Unfortunately, very limited biochemical data are available on this molecule in theliterature [55].O OHHNHOHH HMe2N HONTrichostatin A TRO19622Antibiotics and Their DerivativesAntibiotic aclarubicin was reported to facilitate the retention of exon 7 into theSMN2 transcript.It promoted incorporation of exon 7 into the SMN2 transcripts inType I SMA fibroblasts, bringing the number of SMN gems to normal levels [56] [ Pobierz całość w formacie PDF ]

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