STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa

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Neuromuscular Disorders

Section: Best Results Were Obtained In 6mwt and Fvc Supine Which Could Be Due To A Better Effect Of Ert On The Diaphragmsupporting

confidence: 88%

“…Here, 93% profited in the first years, followed by a secondary decline after three to five years [13]. These results were in line with recent long-term data on ERT in LOPD from Spain, Taiwan, Italy and Germany (STIG study) also showing initial improvement followed by a secondary decline [14]. Some smaller LOPD cohorts showed comparable long-term results [2].…”

supporting

confidence: 87%

Long-term effects of enzyme replacement therapy in an elderly cohort of late-onset Pompe disease

Winkler

Landenberg

Kuchenbecker

et al. 2022

“…Sanofi-Genzyme, Inc. using a rhGAA (alglucosidase alfa) secreted from a CHO cell line has demonstrated moderate success in patients (27), however yearly costs are very high. Although alglucosidase alfa has been a wonderful first step in treating PD it has revealed subtle aspects that must be dealt with for successful treatment (18,(42)(43)(44)(45)(46)(47)(48)(49). ERT usually begins when the patients are symptomatic, however, all the secondary problems are already present which are further compounded by issues with alglucosidase alfa uptake in muscle (Table 7) (18).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies suggest that unchanged endogenous GAA protein expression lowers the chance of forming antibodies to recombinant proteins. Gutschmidt et al (42) found that ERT in late onset patients' clinical outcomes, particularly lung function, muscle strength and walking capability tend to deteriorate over time, indicating that additional efforts must be made to improve ERT effectiveness and supplement therapies developed. Korlimarla et al (43) used a standardized behavior checklists as screening tools for the early identification and treatment of behavior, emotional and social concerns in children with PD.…”

Section: Introductionmentioning

confidence: 99%

Preclinical studies for plant-based oral enzyme replacement therapy (Oral-ERT) in Pompe disease knockout mice with transgenic tobacco seeds expressing human GAA (tobrhGAA)

Mack

et al. 2021

Preprint

Self Cite

Genetic deficiency of acid α-glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe disease (PD) encompassing at least four clinical subtypes of varying severity (infantile; childhood, juvenile and late onset). Our objective is to develop an innovative and affordable approach for enzyme replacement therapy (ERT) via oral administration (Oral-ERT) to maintain a sustained, therapeutic level of enzyme on a daily basis to improve efficacy of treatment and quality of life for people living with Pompe disease. A consensus at a 2019 US Acid Maltase Deficiency (AMDA) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of Pompe disease. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. Previously, we have shown that a lysate from transgenic tobacco seeds expressing human GAA (tobrhGAA) was enzymatically active and can correct enzyme deficiency in cultured PD cells and in adult lymphocytes of Pompe patients and in vivo in disease-relevant tissues in GAA knockout (KO) mice when administered IP.We have extended these pre-clinical studies in PD knockout (KO) mice with ground tobrhGAA seeds that supports proof-of-concept for Oral-ERT for future clinical trials. Briefly in GAA KO mice, Oral-ERT with ground tobrhGAA seeds showed significant reversal of fore-limb and hind-limb muscle weakness, increased motor coordination/balance/strength and mobility, improved spontaneous learning, increased GAA baseline activity in tissues, reduced glycogen in tissues and negible serum titers to GAA. Pharmacokinetics showed maximum serum GAA concentration (Cs) at 8-10 hr and peak urine excretion at 10-12 hr. The tobrhGAA was taken up in PD fibroblast, lymphoid and myoblast cells. Enzyme kinetics compared favorably or superior to placental hGAA, plus alglucosidase alfa or other rhGAAs for Km, Vmax, pH optima, thermal heat stability and IC50 for inhibitors. The tobrhGAA in seeds was extremely stable stored for 15 years at room temperature. NGS-genome sequencing of the tobrhGAA and wild-type plants and RNA expression profiles was performed and will be posted on our website. Thus, Oral-ERT with ground tobrhGAA seeds is an innovative approach that overcomes some of the challenges of alglucosidase alfa-ERT and provides a more effective, safe and significantly less expensive treatment.

“…ERT usually begins when the patients are symptomatic and secondary problems present (41). Gutschmidt et al (42) found that ERT in late onset patients' clinical outcomes, particularly lung function, muscle strength, and walking capability tend to deteriorate over time, indicating that additional efforts must be made to improve alglucosidase alfa's effectiveness and supplement therapies developed. Some patients experienced infusion-associated reactions due to bronchial spasm with flushing and pulmonary artery blockage during infusion.…”

Section: Introductionmentioning

confidence: 99%

Crotamine as a vehicle for non-viral gene delivery for Pompe disease

Mack

et al. 2021

Preprint

Self Cite

Genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in Pompe disease (PD), encompassing at least five clinical subtypes of varying severity. The current approved enzyme replacement therapy (ERT) for PD is via IV infusion every 2 weeks of a recombinant human GAA (rhGAA) secreted by Chinese hamster ovary (CHO) cells (alglucosidase alfa/Myozyme, Sanofi/Genzyme). Although alglucosidase alfa has proven to be efficient in rescuing cardiac abnormalities and extending the life span of the infantile form, the response in skeletal muscle is variable. ERT usually begins when the patients are symptomatic and secondary problems are already present which are compounded by low alglucosidase alfa uptake, transient nature (every 2 weeks with a rapid return to defect levels), variable glycogen reduction, autophagic accumulation, immune response and high cost. A consensus at a recent US Acid Maltase Deficiency (AMD) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of PD. Compared to replication defective viruses, non-viral gene transfer offers fewer safety concerns and, if recent studies are validated, has a wider range of cells. In order for gene therapy (GT) to succeed, the gene of interest must be delivered into the affected cell and expressed to overcome the inherited deficiency. Cell penetrating peptides (CPPs) enter eukaryotic cells through an energy-independent mechanism and efficiently carry biologically active and therapeutic molecules into cells and localize in the cytoplasm or nucleus. CPPs are usually covalently linked to the cargo, including peptides and DNA. Crotamine (Cro) from the South American rattlesnake-Crotalus durrissus terrificus venom, can bind electrostatically to plasmid DNA to deliver into cells, including muscle. We have assembled a bacterial expression vector for Cro and purified the recombinant Cro (rCro). Transient transfection in AMD fibroblasts and ex vivo in whole blood from an adult Pompe patient with rCro complexed with the pcDNA3 x hGAA cDNA demonstrated increased GAA activity. In GAA knockout (KO) mice receiving a single injection of rCro complexed to pcDNA3 x hGAA cDNA intraperitoneally (IP), we found increased GAA activity in tissues after 48 hr. After 8 treatments-IP over 55 days, we found increased vertical hang-time activity, reduced glycogen deposition, increased GAA activity/hGAA plasmid in tissues and minimal immune-reaction to rCro. A subsequent study of 5 administrations every 2 to 3 weeks showed reverse of the clinical phenotypes by running wheel activity, Rotarod, grip-strength meter, open field mobility and T-maze. Tissue culture experiments in PD fibroblast, lymphoid and skeletal muscle cell lines showed increased GAA activity after rCro transient gene delivery.