The aim of this study was to investigate the efficacy of idebenone on neurological function as assessed by ICARS and FARS neurological rating scales in pediatric Friedreich's ataxia (FRDA) patients. ...Sixty-eight pediatric patients were enrolled in an open-label extension study (IONIA-E) where patients received idebenone (Catena
®
, 150 mg film-coated tablets) at a weight-adjusted dose of 1,350/2,250 mg/day for 12 months after patients had completed a double-blind, randomized, placebo-controlled study (IONIA) receiving either idebenone at a weight-adjusted dose of 450/900 or 1,350/2,250 mg/day or placebo for 6 months. Changes in ICARS and FARS total scores and subscores were recorded for the 12-month IONIA-E study and for the 18-month combined IONIA and IONIA-E study period. Data analyzed by a mixed-model repeated-measures ANCOVA relative to baseline resulted in least square means for the change in ICARS for the IONIA-E study of +0.98 points (SEM 0.73;
p
= 0.180), indicating a trend for worsening. However, combined with the IONIA study the change was −1.03 ± 0.68 points (
p
= 0.132), indicating a trend for improvement in neurological function over the 18-month period. Importantly, patients who received idebenone 1,350/2,250 mg/day over this period significantly improved in neurological function (change in ICARS: −3.02 ± 1.22,
p
= 0.014). The improvement in neurological function over time was best seen when the posture and stance subscore was excluded from the analysis. Comparable data were obtained with the FARS. The findings of the open-label IONIA-E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurological function and improving fine motor skills and speech.
Purpose LHON is an inherited mitochondrial orphan disease leading to rapid, irreversible vision loss in the majority patients. This survey reports the clinical course of vision loss and recovery in ...patients with LHON based on a large retrospective data collection.
Methods Visual acuity (VA) data from 383 individual patients were collected by chart review conducted in 11 clinical centres under local ethics approval using a standardized VA report form. Change of VA with time since onset of symptoms was analysed using cross sectional and longitudinal data analyses. Mutation dependent rates for spontaneous clinically relevant recovery (off‐to‐on‐chart or at least 2 lines on chart) of VA were established from 774 individual observations available from 74 patients for whom relevant longitudinal VA data were available for up to 31 months.
Results The data confirm the expected rapid loss of VA with 73% of eyes deteriorating beyond the threshold for legal blindness within 3 months of onset. The VA nadir was typically reached within less than 6 months from onset and for observations available between 12 and 24 months from onset, 78% of eyes remained legally blind. The time to VA recovery and proportion of patients with recovery from nadir varied with the LHON‐associated mtDNA mutation carried. A total of 31.1% patients presented with spontaneous clinically relevant recovery G11778A: 25%, G3460A: 50%, T14484C: 43%).
Conclusion These data demonstrate that in patients with LHON vision loss is rapidly progressive and severe. The great majority of patients do not regain VA but remain legally blind.
Commercial interest
Purpose LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. Here we report visual acuity outcomes for patients ...with recent onset who received Raxone® (idebenone) under an ongoing global Expanded Access Program (EAP).
Methods Visual acuity was measured in 3‐monthly intervals. Clinically relevant recovery was defined as (i) improvement from nadir by at least 10 letters on the ETDRS chart or (ii) improvement from “off‐chart” at nadir to being able to read at least 5 letters on‐chart.
Results Currently there are 61 LHON patients enrolled, of which 48 patients have been treated for an average of 11 months. So far, 24 of 48 patients (50%) have experienced a clinically relevant and stable recovery in VA (89% for T14484C, 70% for G3460A and 31% for G11778A). The average treatment effect size in patients with recovery was 29 letters and 84 % recovered within 12 months of the initiation of the EAP.
Conclusion A high proportion of LHON patients treated with idebenone under a global EAP experienced a clinically meaningful recovery of vision, further demonstrating the therapeutic potential of idebenone in the treatment of LHON.
Commercial interest
We have undertaken an immunological and biochemical analysis of the most abundant soluble protein of previtellogenic Xenopus oocytes, 42S p48. We show that this protein shares immunological ...cross‐reactivity with elongation factor 1 alpha (EF‐1 alpha). Direct assays of both 42S fractions and purified 42S p48 show that this cross‐reactivity is of functional significance since 42S p48, like EF‐1 alpha, can transfer charged amino acids to ribosomes. We further demonstrate that 42S p48 is degraded soon after the onset of vitellogenesis, while the EF‐1 alpha concentration remains essentially unchanged during this transition. These properties of 42S p48 are discussed with regard to its role in oogenesis.
Purpose To establish the long term benefit of oral idebenone 900mg/day in the treatment of Leber's Hereditary Optic Neuropathy (LHON).
Methods Patients who participated in a 24‐week, multi‐centre (3 ...sites), double‐masked, randomized, placebo controlled trial (RHODOS) were re‐assessed at a single visit by means of Visual Acuity (VA) using ETDRS charts.
Results Eighty‐five patients were enrolled in the RHODOS study: 55 treated with idebenone (900mg/day) and 30 with placebo. At the end of the 24 week treatment period, the VA for patients randomized to placebo deteriorated. In contrast, in patients treated with 900mg/day idebenone, VA was preserved. In addition, in severely affected patients with off‐chart vision at Baseline, only idebenone treated patients improved sufficiently to read at least 1 full line on the ETDRS chart (Klopstock et al., 2011). VA was repeated at a follow‐up visit conducted 2.5 years (median) after treatment discontinuation. The difference in VA between placebo and idebenone treated patients was maintained. Specifically, in patients who during RHODOS received idebenone and who on average were protected from vision loss, VA did not deteriorate upon discontinuation of treatment.
Conclusion These findings support the original conclusion that in selected patients with LHON, idebenone has significant therapeutic potential in preventing further vision loss and facilitating vision recovery.
Commercial interest
We have isolated the cDNA for 42Sp48 and EF-1α from mixed stage oocytes and tailbud (stage 22) Xenopus laevis cDNA libraries by use of the cDNA for human elongation factor-1α (EF-1α) as probe. The ...nucleotide and deduced amino acid sequences of the entire coding region of 42Sp48 and EF-1α cDNA were established. The proposed functional homology of the proteins is reflected in highly conserved amino acid sequences (91% identity), while the large number of silent mutations at the gene level may serve to prevent recombination at their loci. 42Sp48 is apparently encoded by two genes in Xenopus, while no sequences corresponding to 42Sp48 could be found in murine or human genomic DNA. 42Sp48 has been proposed to act as a stage-specific elongation factor in Xenopus. Comparison of the deduced amino acid sequences of 42Sp48 and EF-1α with that of elongation factor Tu from E. coli, for which the three-dimensional structure including that of the GTP binding site have been determined, supports this hypothesis.
Two-dimensional gel electrophoretic (NEPHGE) analysis of proteins from mouse 3T3B and 3T3B/SV40 cells labelled with methyl-3Hmethionine in the presence of cycloheximide have revealed that the ...elongation factor 1 alpha (EF-1 alpha) in these cells is methylated and that the extent of methylation is higher in the SV40 transformed cell type. It is suggested that methylation may account for differences in growth properties for the different cell types.
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