Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β<sub>2</sub>-Agonist in Murine Pompe Disease

Han, Sang-oh; Li, Songtao; Bird, Andrew; Koeberl, Dwight D.

doi:10.1089/hum.2015.033

Cited by 14 publications

(13 citation statements)

References 39 publications

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“…We hypothesized that inducing autophagy with a small-molecule drug such as bezafibrate might improve the efficiency of genome editing and increase the long-term correction of G6Pase deficiency in the GSD Ia liver. The cumulative results of this study support that hypothesis and further validate the general hypothesis that combination therapy will enhance the effects of gene therapy 32, 33, 34…”

Section: Discussionsupporting

confidence: 83%

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Kang

Waskowicz

Seifts

et al. 2019

Molecular Therapy - Methods & Clinical Development

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Glycogen storage disease type Ia (GSD Ia) is a rare inherited disease caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene ( G6PC ). Absence of G6Pase causes life-threatening hypoglycemia and long-term complications because of the accumulations of metabolic intermediates. Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, was administered in the context of genome editing with a zinc-finger nuclease-containing vector (AAV-ZFN) and a G6Pase donor vector (AAV-RoG6P). Bezafibrate treatment increased survival and decreased liver size (liver/body mass, p < 0.05) in combination with genome editing. Blood glucose has higher (p < 0.05) after 4 h of fasting, and liver glycogen accumulation (p < 0.05) was lower in association with higher G6Pase activity (p < 0.05). Furthermore, bezafibrate-treated mice had increased numbers of G6PC transgenes (p < 0.05) and higher ZFN activity (p < 0.01) in the liver compared with controls. PPAR-α expression was increased and PPAR-γ expression was decreased in bezafibrate-treated mice. Therefore, bezafibrate improved hepatocellular abnormalities and increased the transduction efficiency of AAV vector-mediated genome editing in liver, whereas higher expression of G6Pase corrected molecular signaling in GSD Ia. Taken together, bezafibrate shows promise as a drug for increasing AAV vector-mediated genome editing.

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Section: Discussionsupporting

confidence: 83%

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Kang

Waskowicz

Seifts

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…This observation was consistent with previous studies showing that AAV vector-mediated expression of GAA increased CI-MPR expression in skeletal muscle without concurrent b2 agonist administration. 12,14 We further analyzed a marker for autophagosome clearance p62, which is increased in the muscle of Pompe patients and normalized by treatment with ERT. 30 Salmeterol treatment significantly decreased p62 in the quadriceps, either alone or in combination with AAV vector administration (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…11 Another b2 agonist, salmeterol, increased the efficacy of an adeno-associated virus (AAV) vector expressing GAA from a ubiquitous promoter by increasing muscle strength of GAA-KO mice, although it only improved biochemical correction in the heart. 12 Previous studies revealed the importance of immune tolerance induction during gene therapy in mice with Pompe disease, [13][14][15] which has been achieved by liver-specific expression of GAA with an AAV vector as described. [16][17][18] In contrast, constitutive expression with a ubiquitous promoter provoked immune responses in GAA-KO mice 16 that might complicate gene therapy in crossreactive immune material-negative patients with Pompe disease, who do not express any residual GAA protein.…”

Section: Introductionmentioning

confidence: 99%

Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease

Han

Everitt

et al. 2019

Human Gene Therapy

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Gene therapy for Pompe disease with adeno-associated virus (AAV) vectors has advanced into early phase clinical trials; however, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up acid a-glucosidase (GAA), has impeded the efficacy of Pompe disease gene therapy. Long-acting selective b2 receptor agonists previously enhanced the CI-MPR expression in muscle. In this study we have evaluated the selective b2 agonist salmeterol in GAA knockout mice in combination with an AAV vector expressing human GAA specifically in the liver. Quadriceps glycogen content was significantly decreased by administration of the AAV vector with salmeterol, in comparison with the AAV vector alone (p < 0.01). Importantly, glycogen content of the quadriceps was reduced to its lowest level by the combination of AAV vector and salmeterol administration. Rotarod testing revealed significant improvement following treatment, in comparison with untreated mice, and salmeterol improved wirehang performance. Salmeterol treatment decreased abnormalities of autophagy in the quadriceps, as shown be lower LC3 and p62. Vector administration reduced the abnormal vacuolization and accumulation of nuclei in skeletal muscle. Thus, salmeterol could be further developed as adjunctive therapy to improve the efficacy of liver depot gene therapy for Pompe disease.

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“…Furthermore, salmeterol improved the biochemical correction of skeletal muscle and enhanced muscle strength in combination with liver depot gene therapy 34 . Although direct transduction of muscle might provide more stable transduction, an AAV vector containing a muscle-specific promoter provoked antibody responses that interfered with the uptake of GAA in uncorrected myofibers 35 . Immunosuppression was beneficial, because glycogen clearance was clearly enhanced by treatment with a nondepleting anti-CD4 monoclonal antibody along with GAA expression in cardiac muscle 35 , 36 .…”

Section: Discussionmentioning

confidence: 99%

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

Han

McCall

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA). It is expected that gene therapy to replace GAA with adeno-associated virus (AAV) vectors will be less effective early in life because of the rapid loss of vector genomes. AAV2/8-LSPhGAA (3 × 1010 vector genomes [vg]/mouse) was administered to infant (2-week-old) or adult (2-month-old) GAA knockout mice. AAV vector transduction in adult mice significantly corrected GAA deficiency in the heart (p < 0.0001), diaphragm (p < 0.01), and quadriceps (p < 0.001) for >50 weeks. However, in infant mice, the same treatment only partially corrected GAA deficiency in the heart (p < 0.05), diaphragm (p < 0.05), and quadriceps (p < 0.05). The clearance of glycogen was much more efficient in adult mice compared with infant mice. Improved wire hang test latency was observed for treated adults (p < 0.05), but not for infant mice. Abnormal ventilation was corrected in both infant and adult mice. Vector-treated female mice demonstrated functional improvement, despite a lower degree of biochemical correction compared with male mice. The relative vector dose for infants was approximately 3-fold higher than adults, when normalized to body weight at the time of vector administration. Given these data, the dose requirement to achieve similar efficacy will be higher for the treatment of young patients.

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Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β₂-Agonist in Murine Pompe Disease

Cited by 14 publications

References 39 publications

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

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Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease

Cited by 14 publications

References 39 publications

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

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Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β₂-Agonist in Murine Pompe Disease