T.P.23 Quantitative evaluation of locoregional high venous pressure rAAV8-U7- ESE6-ESE8 exon-skipping therapy in the GRMD dog using NMR 1H imaging and 31P spectroscopy

Thibaud, Jean-Laurent; Wary, C.; Moullec, Sophie; Azzabou, Noura; Guiner, Caroline Le; García, Laura Carrera; Montus, M.; Chérel, Yan; Fromes, Y.; Servais, Laurent; Roques, Sylvie; Moullier, Philippe; Voït, Thomas; Carlier, Pierre

doi:10.1016/j.nmd.2012.06.188

Cited by 2 publications

(7 citation statements)

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“…Water T 2 and 31 P NMRS indices were visibly altered from the onset of the disease, and may be sensitive to treatment efficacy, as has been observed in corticosteroid therapy in DMD (27) and in exon skipping in GRMD (14).…”

Section: Discussionmentioning

confidence: 79%

“…In the present study, in addition to the quantitative fat fraction, we investigated all parameters which responded in a dose‐dependent manner to exon skipping therapy in the canine GRMD model and which could be assessed non‐invasively by NMR. These were the value and heterogeneity of muscle water T 2 , which characterise inflammation, oedema and tissue disorganisation, and the ratios of phosphate energetic and membrane metabolites by NMRS, which reflect anomalies at the cellular level.…”

Section: Discussionmentioning

confidence: 99%

“…. Unlike quantitative spectroscopic T 2 measurements , T 2 imaging allows the mapping of T 2 and an estimation of its heterogeneity within the muscle, which was found to be a parameter of interest in GRMD .…”

Section: Discussionmentioning

confidence: 99%

“…In GRMD, 31 P spectroscopic approaches have demonstrated the ability to characterise anomalies of dystrophic muscle when compared with control dogs (12,59), and identified the alkaline Pi peak (Pi b ), which also appears in DMD boys (60), and several of these anomalies decreased in a dose-dependent manner with exon therapy (10,14).…”

Section: Fatty Infiltrationmentioning

confidence: 99%

“…In recent trials of exon skipping therapeutic efficacy, T 2 ‐weighted muscle signal heterogeneity, reflecting tissue disorganisation, and maximal relative signal enhancement after injection of gadoteric acid, revealing muscle necrosis and fibrosis, were improved in muscles treated by U7snRNA delivery, and dystrophin expression and muscle strength were partially restored . More recently, both NMRI and NMRS indices have shown dose‐dependent differences between treated and untreated limbs, with NMRI indices related to T 2 heterogeneity and NMRS ratios of inorganic phosphate/phosphocreatine (Pi/PCr), PCr/ATP and phosphodiester (PDE)/(Pi + PCr) showing improvement most proportional to dose .…”

Section: Introductionmentioning

confidence: 99%

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Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy

et al. 2015

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Quantitative NMRI and (31)P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6-18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia ) and an alkaline (Pib) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2 . Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78-100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2 . However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%