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Gene & Protein in Disease Oral-ERT in PD knockout mice with tobrhGAA

5 Veterinary Services Comparative Medicine Resources Office, United States of America
6 Nelson Biological Laboratories Rutgers, The State University of New Jersey, Allison Road, Room D-105 Piscataway, NJ, United States of
America
7 RLATg Veterinary Technician Supervisor Comparative Medicine Resources Rutgers, The State University of New Jersey, D108 Nelson
Biological Laboratories, Allison Road Piscataway, NJ, United States of America
8 Department of Neurology, Friedrich-Baur-Institute, LMU Klinikum, Ludwig-Maximilians-University, Munich, 1, München, Germany
9 Department of Population Health, NYU Langone Medical Center, Smilow Research Center, First Avenue, NY, United States of America
10 West Essex High School, 65 Greenbrook Rd, NJ, United States of America
11 Manhasset High School, 200 Memorial Pl., Manhasset, NY, United States of America
th
12 Columbia University Mailman School of Public Health, West 168 Street, Room 1404, New York, NY, United States of America

1. Introduction 6-phosphate receptor. 15-18 In infants, muscle pathology
and glycogen deposition degree are correlated with
Genetic deficiency of lysosomal acid maltase or acid symptom severity, and the earlier ERT is introduced, the
a-glucosidase (GAA) results in acid maltase deficiency better the chance of response. In patients with adult-
15
or Pompe disease (PD) encompassing at least four clinical onset PD, mild improvements in motor and respiratory
subtypes of varying severity (infantile, childhood, juvenile, functions have been achieved, which are unsatisfactory
and adult-onset). PD is characterized by the intracellular for the reversal of skeletal muscle pathology. 15-18 In
1
accumulation of glycogen in multiple tissues, with skeletal patients with adult-onset PD, the ability of muscles to
muscle being the primary target; moreover, it manifests as metabolize extralysosomal as well as intralysosomal
myopathy and cardiomyopathy. The classic infantile form glycogen is impaired. Lysosomal glycogen accumulation
2-5
of PD is characterized by the absence of enzyme activity, results in multiple secondary abnormalities (autophagy,
muscle weakness, feeding difficulties, and hypertrophic lipofuscin, mitochondria, trafficking, and signaling) that
cardiomyopathy, which leads to death in the 1 year. may improve following long-term therapy. ERT is usually
6-8
st
The adult-onset form of PD has partial enzyme deficiency initiated when the patients are symptomatic and these
that manifests with slow, progressive muscle weakness, secondary problems are already present, which contributes
which leads to wheelchair/ventilator dependence and to inefficient delivery and uptake of alglucosidase alfa
premature death from ventilatory insufficiency. 9-11 The in the muscles. The outcome of infantile patients is
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incidence of people living with PD is estimated at 1:40,000 determined by numerous factors, including age, disease
(Orpha number: ORPHA365 at www.orpha.net). Park severity at ERT commencement, genotype, genotype-
13
12
recalculated the carrier frequency (pCF) and predicted dependent cross-reactive immunological material (CRIM)
genetic prevalence (pGP) using general population status, and antibody response level. High and sustained
databases based on the causative genotype proportions. antibody titers need to be prevented to achieve a good
Total pCF and pGP were 1.3% (1 in 77) and 1:23,232, response to ERT; however, titers vary substantially among
respectively. Recently, Colburn and Lapidus reviewed the patients and do not strictly correlate with the patients’
literature for over 11.6 million newborns screened for PD CRIM status. Approximately 40% of infantile patients are
from 29 screening programs across eight countries and CRIM-negative, whereas the remaining 60% are CRIM-
four continents. The birth prevalence of PD was 1:18,711, positive. The immune response may be minimized by
with no evidence of difference across European, Latin the early commencement of ERT and pretreatment with
American, and Asian populations; however, differences an immune tolerance induction regimen, such as using a
may exist in the PD subtypes. 14 combination of rituximab, methotrexate, bortezomib, and
Enzyme replacement therapy (ERT) with a recombinant IV immunoglobulins. Up to 20% of adult patients develop
human GAA (rhGAA) secreted by Chinese hamster ovary high titers when receiving ERT, 40% develop intermediate
(CHO) cells (alglucosidase alfas; Myozyme from Genzyme; titer levels, and 40% develop none or low titers. 20-37 In most
Lumizyme from Sanofi Corp) infused every 2 weeks patients with adult-onset PD, antibody formation does not
was the first approved therapy. Although it is efficient in interfere with rhGAA efficacy. 38-41 Gutschmidt et al. found
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rescuing cardiac abnormalities and extending the life that the clinical outcomes of ERT in patients with late-
span of infants, the response of skeletal muscle varies onset PD, particularly lung function, muscle strength, and
(marketed dose of 20 mg/kg/every 2 weeks administered walking capability, tend to deteriorate over time, indicating
intravenously) through the cation-independent mannose that additional efforts must be made to improve the

Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.1760