Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies

Baik, Andrew D.; Calafati, Philip; Zhang, Xiaoli; Aaron, Nina; Mehra, Antonia; Moller-Tank, Sven; Miloscio, Lawrence; Praggastis, Maria; Giovannone, Nicholas; Pan, Cheryl; Tang, Yajun; Bridges, Susannah; Mujica, Alejo; Barbounis, Peter; Yanolatos, Jean; Gale, Nicholas W.; Li, Ning; Kyratsous, Christos A.; Schoenherr, Christopher J.; Murphy, Andrew; Economides, Aris N.; Cygnar, Katherine D.

doi:10.1016/j.ymthe.2021.08.020

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…Similar findings happened when using a single-chain fragment variable (scFv) instead of IgG. In a second step, the same study used AAV2/8 viruses encoding α-hCD63 1 scFv:GAA driven by a liver-specific promoter and showed higher GAA levels compared to AAV-GAA treated mice [124 ▪ ]. A similar strategy was used to create VAL-1221, a fusion protein comprising the Fab portion of a cell penetrating-antibody and rhGAA, tested in a 3-month phase I/II study in 12 adults with LOPD.…”

Section: Other Treatment Approachesmentioning

confidence: 62%

Current avenues of gene therapy in Pompe disease

Leon-Astudillo,

Trivedi,

Sun

et al. 2023

Current Opinion in Neurology

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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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Section: Other Treatment Approachesmentioning

confidence: 62%

Current avenues of gene therapy in Pompe disease

Leon-Astudillo,

Trivedi,

Sun

et al. 2023

Current Opinion in Neurology

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“…The effective transduction of the GAA gene to the heart and muscle is very important for drug efficacy. The liver is the organ with the most abundant AAV after systematic administration because of its rich blood supply; sustainably expressed GAA in the liver can be secreted into the blood and taken up by muscles and other peripheral organs to reinforce the efficacy [ 22 , 23 ]. As demonstrated in Figure 1 , GC301 was widely distributed in the heart, liver, and muscles.…”

Section: Discussionmentioning

confidence: 99%

Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials

Wang,

Zhang,

Dong

et al. 2024

Viruses

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The efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used for patient enroll; however, this assay could not evaluate NAbs’ impacts on AAV pharmacology and potential harm in vivo. Here, we infused a mouse anti-AAV9 monoclonal antibody into Balb/C mice 2 h before receiving 1.2 × 1014 or 3 × 1013 vg/kg of rAAV9-coGAA by tail vein, a drug for our ongoing clinical trials for Pompe disease. The pharmacokinetics, pharmacodynamics, and cellular responses combined with in vitro NAb assay validated the different impacts of preexisting NAbs at different levels in vivo. Sustained GAA expression in the heart, liver, diaphragm, and quadriceps were observed. The presence of high-level NAb, a titer about 1:1000, accelerated vector clearance in blood and completely blocked transduction. The AAV-specific T cell responses tended to increase when the titer of NAb exceeded 1:200. A low-level NAbs, near 1:100, had no effect on transduction in the heart and liver as well as cellular responses, but decreased transduction in muscles slightly. Therefore, we propose to preclude patients with NAb titers > 1:100 from rAAV9-coGAA clinical trials.

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“… 33 , 41 In another study, an antibody domain fused to GAA targeting CD63 was effective in delivery through ERT and liver-directed AAV gene therapy to skeletal muscles as well. 75 Besides using the liver as a depot for effective correction of skeletal muscle, 76 muscle-directed AAV gene therapy has also shown efficacious effects. 77 Importantly, in a clinical trial directing AAV1 serotype to the diaphragm, gene therapy led to an increase in subject tolerance for duration of unassisted breathing, 12 showing potential for AAV gene therapy to treat Pompe disease.…”

Section: Discussionmentioning

confidence: 99%