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ORIGINAL RESEARCH ARTICLE

Pre-clinical studies for oral enzyme replacement therapy in Pompe disease knockout mice with tobacco seeds expressing human GAA

Frank Martiniuk1,2* ,  Adra Mack1,2 ,  Justin Martiniuk1,2 ,  Gregory O. Voronin3 ,  Shoreh Miller4 ,  David Reimer5 ,  Nancy Rossi6 ,  Leslie Sheppard Bird7 ,  Sussan Saleh7 ,  Ruby Gupta7 ,  Mariel Nigro7 ,  Peter Meinke8 ,  Benedikt Schoser8 ,  Feng Wu9 ,  Angelo Kambitsis1,2 ,  John Arvanitopoulos1,2 ,  Elena Arvanitopoulos1,2 ,  Pavlos Arvanitopoulos10 ,  Alexander Demetriades11 ,  Kam-Meng Tchou-Wong12
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1 JME Group Associates, Inc, 24 Ford Lane, Roseland, NJ, United States of America
2 PsychoGenetics Center, 215 College Rd., Lab 213, Paramus, NJ, United States of America
3 In Vivo Research Services Rutgers, The State University of New Jersey, United States of America
4 Department of Pediatric, RWJMS Director, In Vivo Research Services (IVRS) Rutgers University Animal Care U (RUAC) Rutgers, the State University of New Jersey Rm 017, CABM 679 Hoes Lane West Piscataway, NJ, United States of America
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
12 Columbia University Mailman School of Public Health, West 168th Street, Room 1404, New York, NY, United States of America
GPD, 1760 https://doi.org/10.36922/gpd.1760
Submitted: 5 September 2023 | Accepted: 20 June 2024 | Published: 2 January 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Genetic deficiency of acid a-glucosidase (GAA) results in Pompe disease (PD) encompassing four clinical subtypes of varying severity. Our objective is to develop an innovative and affordable approach for enzyme replacement therapy (ERT) through oral administration (Oral-ERT) to maintain a sustained therapeutic level of enzyme daily to improve treatment efficacy. Tobacco seeds contain the metabolic machinery compatible with mammalian glycosylation-phosphorylation. We have shown that transgenic tobacco seeds expressing human GAA (tobrhGAA) were enzymatically active and can correct the enzyme deficiency in cultured cells and in GAA knockout (GAAKO) mice administered IP. We have extended these studies in PD KO mice with ground tobrhGAA seeds. Briefly, in PD knockout mice, Oral-ERT with ground tobrhGAA seeds showed a significant reversal of fore-limb and hind-limb muscle weakness, increased motor coordination/balance/strength/mobility, improved spontaneous learning, increased GAA activity in tissues, reduced glycogen in tissues and negligible serum titers to GAA. Pharmacokinetics showed maximum serum GAA concentration at 8 – 10 h and peak urine excretion at 10 – 12 h post-administration. The tobrhGAA was taken up in PD fibroblast, lymphoid, and myoblast cells. Enzyme kinetics compared favorably to hGAA, plus alglucosidase alfa or other recombinant human GAAs for Km, Vmax, pH optima, thermal heat stability, and IC50 for inhibitors. The tobrhGAA in seeds was stable for 15 years at room temperature. 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.

Keywords
Recombinant human acid maltase
Transgenic tobacco plants
Pompe disease
Oral enzyme replacement
Funding
This study was supported in part by the NIH-SBIR Phase I grant-Oral-ERT of PD with Tobacco Seed-Derived Recombinant Acid Maltase RFA-AR-18-005 grant #1R43AR073522-01.
Conflict of interest
The authors declare they have no competing interests.
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