Current Avenues of Gene Therapy in Pompe Disease

Overview

Journal Curr Opin Neurol

Specialty Neurology

Date 2023 Aug 28

PMID 37639402

Authors

Carmen Leon-Astudillo

Prasad D Trivedi

Ramon C Sun

Matthew S Gentry

David D Fuller

Barry J Byrne

Manuela Corti

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions.

Recent Findings: Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability.

Summary: Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing.

Citing Articles

Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.

Fuller D, Rana S, Thakre P, Benevides E, Pope M, Todd A bioRxiv. 2025; .

PMID: 39763722 PMC: 11702543. DOI: 10.1101/2024.12.10.627800.

A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.

Holt B, Elliott S, Meyer R, Reyes D, ONeil K, Druzina Z Mol Ther. 2024; 33(1):235-248.

PMID: 39604266 PMC: 11764773. DOI: 10.1016/j.ymthe.2024.11.033.

Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy.

Colella P Mol Diagn Ther. 2024; 28(6):703-719.

PMID: 39134822 DOI: 10.1007/s40291-024-00733-x.

Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy.

Pidaparti M, Geddes G, Durbin M J Clin Med. 2024; 13(9).

PMID: 38731073 PMC: 11084871. DOI: 10.3390/jcm13092544.

References

Lim J, Li L, Shirihai O, Trudeau K, Puertollano R, Raben N . Modulation of mTOR signaling as a strategy for the treatment of Pompe disease. EMBO Mol Med. 2017; 9(3):353-370. PMC: 5331267. DOI: 10.15252/emmm.201606547. View

Costa Verdera H, Kuranda K, Mingozzi F . AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol Ther. 2020; 28(3):723-746. PMC: 7054726. DOI: 10.1016/j.ymthe.2019.12.010. View

Cohen J, Chakraborty P, Fung-Kee-Fung K, Schwab M, Bali D, Young S . In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease. N Engl J Med. 2022; 387(23):2150-2158. PMC: 10794051. DOI: 10.1056/NEJMoa2200587. View

Smith B, Martin A, Lawson L, Vernot V, Marcus J, Islam S . Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity. Exp Neurol. 2016; 287(Pt 2):216-224. PMC: 5178134. DOI: 10.1016/j.expneurol.2016.07.013. View

Mah C, Pacak C, Cresawn K, DeRuisseau L, Germain S, Lewis M . Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007; 15(3):501-7. DOI: 10.1038/sj.mt.6300100. View

Elmallah M, Falk D, Nayak S, Federico R, Sandhu M, Poirier A . Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice. Mol Ther. 2013; 22(4):702-12. PMC: 3982493. DOI: 10.1038/mt.2013.282. View

Teener J . Late-onset Pompe's disease. Semin Neurol. 2013; 32(5):506-11. DOI: 10.1055/s-0033-1334469. View

Kyosen S, Iizuka S, Kobayashi H, Kimura T, Fukuda T, Shen J . Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction. Gene Ther. 2009; 17(4):521-30. DOI: 10.1038/gt.2009.160. View

Ziegler R, Bercury S, Fidler J, Zhao M, Foley J, Taksir T . Ability of adeno-associated virus serotype 8-mediated hepatic expression of acid alpha-glucosidase to correct the biochemical and motor function deficits of presymptomatic and symptomatic Pompe mice. Hum Gene Ther. 2008; 19(6):609-21. DOI: 10.1089/hum.2008.010. View

10.

Todd A, McElroy J, Grange R, Fuller D, Walter G, Byrne B . Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease. Ann Neurol. 2015; 78(2):222-34. PMC: 4520217. DOI: 10.1002/ana.24433. View

11.

Lesch H, Heikkila K, Lipponen E, Valonen P, Muller A, Rasanen E . Process Development of Adenoviral Vector Production in Fixed Bed Bioreactor: From Bench to Commercial Scale. Hum Gene Ther. 2015; 26(8):560-71. DOI: 10.1089/hum.2015.081. View

12.

Sun B, Zhang H, Franco L, Brown T, Bird A, Schneider A . Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter. Mol Ther. 2005; 11(6):889-98. DOI: 10.1016/j.ymthe.2005.01.012. View

13.

Foust K, Nurre E, Montgomery C, Hernandez A, Chan C, Kaspar B . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2008; 27(1):59-65. PMC: 2895694. DOI: 10.1038/nbt.1515. View

14.

Sun B, Brooks E, Koeberl D . Preclinical Development of New Therapy for Glycogen Storage Diseases. Curr Gene Ther. 2015; 15(4):338-47. PMC: 4682885. DOI: 10.2174/1566523215666150630132253. View

15.

Grieger J, Soltys S, Samulski R . Production of Recombinant Adeno-associated Virus Vectors Using Suspension HEK293 Cells and Continuous Harvest of Vector From the Culture Media for GMP FIX and FLT1 Clinical Vector. Mol Ther. 2015; 24(2):287-297. PMC: 4817810. DOI: 10.1038/mt.2015.187. View

16.

Elder M, Nayak S, Collins S, Lawson L, Kelley J, Herzog R . B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr. 2013; 163(3):847-54.e1. PMC: 3981605. DOI: 10.1016/j.jpeds.2013.03.002. View

17.

van der Wal E, Bergsma A, Pijnenburg J, van der Ploeg A, Pijnappel W . Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease. Mol Ther Nucleic Acids. 2017; 7:90-100. PMC: 5415969. DOI: 10.1016/j.omtn.2017.03.001. View

18.

Smith B, Allen S, Mays S, Martin A, Byrne B . Dynamic respiratory muscle function in late-onset Pompe disease. Sci Rep. 2019; 9(1):19006. PMC: 6908708. DOI: 10.1038/s41598-019-54314-8. View

19.

Salabarria S, Nair J, Clement N, Smith B, Raben N, Fuller D . Advancements in AAV-mediated Gene Therapy for Pompe Disease. J Neuromuscul Dis. 2019; 7(1):15-31. PMC: 7029369. DOI: 10.3233/JND-190426. View

20.

Gonzalez T, Simon K, Blondel L, Fanous M, Roger A, Maysonet M . Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing. Nat Commun. 2022; 13(1):5947. PMC: 9548504. DOI: 10.1038/s41467-022-33745-4. View