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The effects of sub-maximal aerobic exercise in adults with late-onset Pompe disease (LOPD)

1/2 pediatric trials are ongoing. We present a quantitative systems
pharmacology (QSP) model to support the development of olipudase
alfa. The model utilizes a mechanistic, multi-scale approach to link
the enzymatic activity deciency driving ASMD with consequent
lipid accumulation, cellular abnormalities, and organ-level clinical
manifestations. The QSP model was developed by integrating
knowledge from ASMD natural history, preclinical, and clinical data,
and takes as input patient-specic PK proles and indicators of
disease severity. The model successfully reproduces both transient
and long-term patient-specic responses to olipudase alfa. At the
molecular level, it describes plasma ceramide and dried blood spot
lyso-sphingomyelin proles; at the organ level, it describes spleen
volume and pulmonary function. Overall, the QSP model enables
quantitative representation of systemic treatment responses to
olipudase alfa. Due to the clinical heterogeneity of ASMD, this
provides insight into treatment effects on different aspects of the
overall disease burden, as a function of patient variability. The QSP
model provides a platform for addressing clinical questions of
interest such as alternative dosing regimens, patient stratication,
and pediatric extrapolation.
[1] McGovern et al. (2013) Genet Med. 15(8):618-623.
[2] Wasserstein et al. (2015) Mol Genet Metab. 116(1-2):88-97.
[3] Thurberg et al. (2016) Am J Surg Pathol. 40(9):1232-1242.
The effects of sub-maximal aerobic exercise in adults with
late-onset Pompe disease (LOPD)
Ayfer Kahraman
, Elaine M. Murphy
, Robin H. Lachmann
, Chris
, Stephen Dando
, Mark Roberts
, Edward Silk
UCLH, London, United Kingdom,
UCLH, London, United Kingdom,
Salford Royal NHS Foundation Trust, Manchester, United Kingdom
Effectiveness of enzyme replacement therapy (ERT) is well
documented in patients with LOPD. Positive effects of sub-maximal
(70%HRmax) exercise in LOPD are also emerging. This pilot study
explored whether an individualised, sub-maximal exercise program
alongside ERT improved walking (6-minute walking test (6MWT)),
respiratory function (Forced Vital Capacity (FVC)) and overall
functional ability (Quick Motor Function Test (QMFT)) over 6
months. Adults (n=11) with LOPD, on ERT for at least 12 months,
able to walk N50m, and able to safely transfer were randomized
to either cycling-between or cycling-during ERT infusions with
an individualised cycling prescription. Outcome measures were
assessed at baseline, 3 and 6 months. Signicant changes were
observed in mean walking distance in the cycling-during ERT group
(n=4) (mean baseline= 397m, end-point= 497m, change=
+101m). These patients improved their walking distance by +26%,
+179%, +18%, and +6% respectively (Minimal Clinically Important
Difference (MCID) = 6%). In the cycling-between ERT group (n= 7)
mean walking distance remained stable (baseline= 428m, end-
point= 429m). In the cycling-during ERT group two patients
signicantly improved FVC by 6% and 16% (MCID = 6%). In the
cycling-between ERT group two patients signicantly improved
their FVC by 8% and 10% (MCID = 6%). Changes in mean FVC were
not signicant in either group. Overall functional ability (QMFT)
improved in both groups. In LOPD, sub-maximal exercise during ERT
signicantly affects walking distance. Exercise, either during or
between infusions, in addition to ERT, demonstrates stabilization of
disease over 6 months with modest functional improvements. This
pilot study supports previous ndings regarding the positive effects
of ERT and exercise on pulmonary function and functional activities.
(This study was funded by SanoGenzyme.)
AAAV5-mediated gene therapy with choroid plexus-directed
α-n-acetyl-glucosaminidase expression in Sanlippo syndrome
type B mice
Shih-hsin Kan, Steven Q. Le, Patricia I. Dickson, Los Angeles Biomedical
Research Institute at Harbor-UCLA, Torrance, CA, United States
Mucopolysaccharidosis type IIIB (MPS IIIB; Sanlippo syndrome
type B) is an inherited neurodegenerative disorder for which has
no effective treatment currently. The cause of Sanlippo syndrome
type B is the deciency of a lysosomal enzyme, α-N-acetyl-
glucosaminidase (NAGLU) and resultant the storage of heparan
sulfate. Current studies have shown that intracerebroventricular
(ICV) enzyme replacement therapy (ERT) with IGF-2 fusion protein
is a feasible treatment mouse model. It overcomes two impediments
to ERT: the absence of mannose 6-phosphate (M6P) on recombinant
human NAGLU (rhNAGLU) and the blood brain barrier. In this study,
we administered a recombinant adeno-associated virus, serotype 5
(AAV5) vector expressing hNAGLU or hNAGLU-IGF2 that targets the
choroid plexus epithelia to produce the missing enzyme into the
cerebrospinal uid (CSF) which will distribute hNAGLU throughout
the brain in the mouse model. 2.5x10
vector genomes (v.g.) of
rAAV5 was administered into ventricles bilaterally in MPS IIIB mice
at postnatal day 1 or 2. NAGLU activity reached 2-8 fold of control
level in the brain section around the injection site after 6 weeks and
0.25 folds after 10 months post-treatment with rAAV5-hNAGLU.
Hexosaminidase activity, which is elevated in MPS IIIB mice, was
stably reduced to carrier levels in most of the brain areas except in
cerebrum and brainstem 10 months after treatment. Immunohisto-
chemistry demonstrated the expression of hNAGLU in the choroid
plexus epithelia and signicant reduction of Lamp1 expression in the
treated mice. Partial hexosaminidase activity reduction was observed
in animals treated with rAAV5-hNAGLU-IGF2. Although no detect-
able NAGLU activity in liver in either treated group was measured,
hexosaminidase activity was partially reduced in rAAV5-hNAGLU
treated mice. Choroid plexus-targeted viral gene therapy with
rAAV5-hNAGLU has the potential to provide long-term, efcient
treatment of the brain for Sanlippo syndrome type B.
PQ-interval and QRS duration increased in Fabry patients treated
by enzyme replacement therapy for 12 years
Ilkka Kantola
, Antti-Pekka Annala
, Tiina Helio
, Aki Hietaharju
Taru Kantola
, Kristiina Kananen
, Anne Karhu
, Jorma Kokkonen
Johanna Kuusisto
, Paivi Pietila-Effati
, Miia Rainto
, Jukka Saarinen
Lorenzo Sandini
, Markku Savolainen
, Jyrki Taurio
, Pentti Tienari
Susanne Walls
, Kati Valtola
Turku University Hospital, Turku,
Seinajoki Central Hospital, Seinajoki, Finland,
University Central Hospital, Helsinki, Finland,
Tampere University
Hospital, Tampere, Finland,
Kainuu Central Hospital, Kajaani, Finland,
Satakunta Central Hospital, Pori, Finland,
Central Finland Central
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17S145 S73
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