TY - ABST

T1 - Effect of intrathecal recombinant human arylsulfatase A enzyme replacement therapy on structural brain MRI in children with metachromatic leukodystrophy

AU - Groeschel, Samuel

AU - Amedick, Lucas Bastian

AU - Hanson, L.G.

AU - Wu, James

AU - Jacobsen, Leslie

AU - Port, John

PY - 2020/2

Y1 - 2020/2

N2 - Metachromatic leukodystrophy (MLD) is a rare neurometabolic disorder caused by arylsulfatase A (ASA) deficiency, resulting in sulfatide accumulation, demyelination and rapid neurological dete- rioration. A phase 1/2 study (NCT01510028) recently assessed the safety of intrathecal (IT) recombinant human ASA (rhASA; TAK-611, formerly SHP611) in children with MLD aged 19–107 months. This retrospective analysis investigated the effect of IT rhASA on brain tissue changes in children with MLD using MRI volumetric and diffusion indices. 170 MRIs of 24 children with MLD treated with IT rhASA (NCT01510028) were compared with 56 MRIs of 12 children with MLD treated with intravenous (IV) rhASA (NCT00418561/ NCT00633139), 43 MRIs of 33 untreated children with MLD and 202 MRIs of 120healthy controls. Automated segmentation of gray matter (GM) and white matter (WM) volumes was performed using T1- and T2-weighted sequences. Fractional anisotropy (FA) was calculated from diffusion tensor imaging in the frontal WM and part of the pyramidal tract. Brain volume, GM volume and FA in all regions were decreased in children with MLD vs age-matched healthy controls. The most pronounced effects were visible for total brain and GM volume, and FA in the pyramidal tract, with greater decreases in the untreated and IV rhASA groups vs the IT rhASA group (P b .05). Children treated with 100 mg IT rhASA every other week (EOW) who maintained or improved their baseline motor function had improved MRI indices compared with those who declined. GM volume and microstructural changes in the pyramidal tract deteriorated over the clinical course in children with MLD. IT rhASA treatment had a positive effect on brain tissue changes. These MRI indices correlated with clinical response to treatment with 100 mg IT rhASA EOW. Shire (a Takeda company) funded this study and writing support.

AB - Metachromatic leukodystrophy (MLD) is a rare neurometabolic disorder caused by arylsulfatase A (ASA) deficiency, resulting in sulfatide accumulation, demyelination and rapid neurological dete- rioration. A phase 1/2 study (NCT01510028) recently assessed the safety of intrathecal (IT) recombinant human ASA (rhASA; TAK-611, formerly SHP611) in children with MLD aged 19–107 months. This retrospective analysis investigated the effect of IT rhASA on brain tissue changes in children with MLD using MRI volumetric and diffusion indices. 170 MRIs of 24 children with MLD treated with IT rhASA (NCT01510028) were compared with 56 MRIs of 12 children with MLD treated with intravenous (IV) rhASA (NCT00418561/ NCT00633139), 43 MRIs of 33 untreated children with MLD and 202 MRIs of 120healthy controls. Automated segmentation of gray matter (GM) and white matter (WM) volumes was performed using T1- and T2-weighted sequences. Fractional anisotropy (FA) was calculated from diffusion tensor imaging in the frontal WM and part of the pyramidal tract. Brain volume, GM volume and FA in all regions were decreased in children with MLD vs age-matched healthy controls. The most pronounced effects were visible for total brain and GM volume, and FA in the pyramidal tract, with greater decreases in the untreated and IV rhASA groups vs the IT rhASA group (P b .05). Children treated with 100 mg IT rhASA every other week (EOW) who maintained or improved their baseline motor function had improved MRI indices compared with those who declined. GM volume and microstructural changes in the pyramidal tract deteriorated over the clinical course in children with MLD. IT rhASA treatment had a positive effect on brain tissue changes. These MRI indices correlated with clinical response to treatment with 100 mg IT rhASA EOW. Shire (a Takeda company) funded this study and writing support.

U2 - 10.1016/j.ymgme.2019.11.161

DO - 10.1016/j.ymgme.2019.11.161

M3 - Conference abstract in journal

VL - 129

SP - S68-S68

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 2

M1 - 152

T2 - Advances in Rare Lysosomal Storage Disorders at 16th Annual WORLDSymposium 2020

Y2 - 10 February 2020 through 13 February 2020

ER -