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Review
. 2023 Oct 1;36(5):464-473.
doi: 10.1097/WCO.0000000000001187. Epub 2023 Jul 19.

Current avenues of gene therapy in Pompe disease

Carmen Leon-Astudillo  1 , Prasad D Trivedi  1 , Ramon C Sun  2   3   4 , Matthew S Gentry  2   3   4 , David D Fuller  5   6 , Barry J Byrne  1 , Manuela Corti  1
Affiliations
Review

Current avenues of gene therapy in Pompe disease

Carmen Leon-Astudillo et al. Curr Opin Neurol. .

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.

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Conflict of interest statement

Conflicts of interest

RCS has received research support and received consultancy fees from Maze Therapeutics and is a member of the Medical Advisory Board for Little Warrior Foundation. MSG has research support, research compounds, or consultancy fees from Maze Therapeutics, Valerion Therapeutics, Ionis Pharmaceuticals, PTC Therapeutics, and the Glut1-Deficiency Syndrome Foundation. RCS and MSG are co-founders of Attrogen LLC. MC has received research support from Sanofi, Friedreich Ataxia Research Alliance (FARA), Amicus, AavantiBio, Lacerta, Provention Bio, Sarepta, Duchenne Research Fund, Muscular Dystrophy Association (MDA), GoFAR, Cydan, Audentes. MC has received consulting fees from AavantiBio, Reata, Lilly, Avexis and Gilbert foundation, SwanBio and PCT Therapeutics. BJB has received research support from SolidBio, ProventionBio, Barth Syndrome Foundation. BJB has received consulting fees from AavantiBio, Amicus Therapeutics, Rocket Pharma, Pfizer, Sanofi, and Sarepta Therapeutics. MC and BB are co-founders of Ventura, LLC.

Figures

Figure 1.
Figure 1.
Timeline of the most relevant clinical trials using enzyme replacement therapy (left) and Adeno-associated viral vectors (right). IOPD: Infantile-onset Pompe disease. LOPD: Late-onset Pompe disease. IV: intravenous. IM: Intramuscular. TA: tibialis anterior. vgs: vector genomes
Figure 2.
Figure 2.
Summary of all in-vivo and ex-vivo vectors and promoters reported based on tissue tropism. CNS: Central nervous system. HSPC: Hematopoietic stem and progenitor cell
Figure 3.
Figure 3.
Preclinical and clinical strategies to treat Pompe disease. ERT: enzyme replacement therapy, GAA: acid alfa glucosidase. M6P: Mannose-6-Phosphate. GYS 1: Glycogen synthase 1
See this image and copyright information in PMC

References

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