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Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease.

Wang G, Young SP, Bali D, Hutt J, Li S, Benson J, Koeberl DD - Mol Ther Methods Clin Dev (2014)

Bottom Line: The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females.Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced.The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue.

View Article: PubMed Central - PubMed

Affiliation: Applied Toxicology and Gene Therapy Pharm/Tox Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.

ABSTRACT
A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid α-glucosidase (rhGAA, Myozyme) enzyme replacement treatment (ERT) for patients with Pompe disease (AAV2/8-LSPhGAApA). The AAV2/8-LSPhGAApA vector at 1.6 × 10(13) vector particles/kg, after intravenous injection, did not cause significant short- or long-term toxicity. Recruitment of CD4(+) (but not CD8(+)) lymphocytes to the liver was elevated in the vector-dosed male animals at study day (SD) 15, and in group 8 animals at SD 113, in comparison to their respective control animals. Administration of the vector, either prior to or after the one ERT injection, uniformly prevented the hypersensitivity induced by subsequent ERT in males, but not always in female animals. The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females. Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced. The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue. Given the lack of toxicity for AAV2/8LSPhGAApA, further consideration of clinical translation is warranted in Pompe disease.

No MeSH data available.


Related in: MedlinePlus

Serum biomarkers. (a) Creatine kinase. (b) Aspartate aminotransferase. (c) Glucose. (d) Triglycerides. Mean ± SD is shown. *P < 0.05. Group: 3, vehicle; 4, vector; 5, vector, ERT ×2; 6, ERT ×2; 7, vector, ERT ×8; 8, ERT, vector, ERT ×5. ERT, enzyme replacement treatment.
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fig5: Serum biomarkers. (a) Creatine kinase. (b) Aspartate aminotransferase. (c) Glucose. (d) Triglycerides. Mean ± SD is shown. *P < 0.05. Group: 3, vehicle; 4, vector; 5, vector, ERT ×2; 6, ERT ×2; 7, vector, ERT ×8; 8, ERT, vector, ERT ×5. ERT, enzyme replacement treatment.

Mentions: Vector administration was associated with lower serum creatine kinase (Figure 5a), and aspartate aminotransferase (Figure 5b), consistent with effective correction of Pompe disease. At SD 113, the serum aspartate aminotransferase level was found significantly lower in vector-treated males from groups 4, 5, 7, and 8, and also in group 7 and 8 females as compared to the vehicle-treated group 3 control females. Serum creatine kinase was significantly reduced in the vector-treated females in group 7 and males in group 8. Since the elevation of creatine kinase and aspartate aminotransferase is listed as clinical signs in infants with Pompe disease,8 the reductions in creatine kinase and aspartate aminotransferase were deemed the result of the therapeutic effect of the vector administration ± ERT in those groups. In addition, the glucose level was significantly lower in vector-treated female mice from groups 5, 6, 7, and 8, and also ERT-treated male mice from group 6, in comparison to vehicle-treated mice in group 3 (Figure 5c). The glucose level change is speculated to be associated with response to the treatment of a GAA supplement, although the glucose elevation was not seen in all male mice following ERT. Finally, triglycerides were significantly lower in vehicle-treated mice of both sexes from group 8 (Figure 5d), suggesting a treatment effect.


Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease.

Wang G, Young SP, Bali D, Hutt J, Li S, Benson J, Koeberl DD - Mol Ther Methods Clin Dev (2014)

Serum biomarkers. (a) Creatine kinase. (b) Aspartate aminotransferase. (c) Glucose. (d) Triglycerides. Mean ± SD is shown. *P < 0.05. Group: 3, vehicle; 4, vector; 5, vector, ERT ×2; 6, ERT ×2; 7, vector, ERT ×8; 8, ERT, vector, ERT ×5. ERT, enzyme replacement treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362383&req=5

fig5: Serum biomarkers. (a) Creatine kinase. (b) Aspartate aminotransferase. (c) Glucose. (d) Triglycerides. Mean ± SD is shown. *P < 0.05. Group: 3, vehicle; 4, vector; 5, vector, ERT ×2; 6, ERT ×2; 7, vector, ERT ×8; 8, ERT, vector, ERT ×5. ERT, enzyme replacement treatment.
Mentions: Vector administration was associated with lower serum creatine kinase (Figure 5a), and aspartate aminotransferase (Figure 5b), consistent with effective correction of Pompe disease. At SD 113, the serum aspartate aminotransferase level was found significantly lower in vector-treated males from groups 4, 5, 7, and 8, and also in group 7 and 8 females as compared to the vehicle-treated group 3 control females. Serum creatine kinase was significantly reduced in the vector-treated females in group 7 and males in group 8. Since the elevation of creatine kinase and aspartate aminotransferase is listed as clinical signs in infants with Pompe disease,8 the reductions in creatine kinase and aspartate aminotransferase were deemed the result of the therapeutic effect of the vector administration ± ERT in those groups. In addition, the glucose level was significantly lower in vector-treated female mice from groups 5, 6, 7, and 8, and also ERT-treated male mice from group 6, in comparison to vehicle-treated mice in group 3 (Figure 5c). The glucose level change is speculated to be associated with response to the treatment of a GAA supplement, although the glucose elevation was not seen in all male mice following ERT. Finally, triglycerides were significantly lower in vehicle-treated mice of both sexes from group 8 (Figure 5d), suggesting a treatment effect.

Bottom Line: The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females.Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced.The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue.

View Article: PubMed Central - PubMed

Affiliation: Applied Toxicology and Gene Therapy Pharm/Tox Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.

ABSTRACT
A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid α-glucosidase (rhGAA, Myozyme) enzyme replacement treatment (ERT) for patients with Pompe disease (AAV2/8-LSPhGAApA). The AAV2/8-LSPhGAApA vector at 1.6 × 10(13) vector particles/kg, after intravenous injection, did not cause significant short- or long-term toxicity. Recruitment of CD4(+) (but not CD8(+)) lymphocytes to the liver was elevated in the vector-dosed male animals at study day (SD) 15, and in group 8 animals at SD 113, in comparison to their respective control animals. Administration of the vector, either prior to or after the one ERT injection, uniformly prevented the hypersensitivity induced by subsequent ERT in males, but not always in female animals. The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females. Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced. The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue. Given the lack of toxicity for AAV2/8LSPhGAApA, further consideration of clinical translation is warranted in Pompe disease.

No MeSH data available.


Related in: MedlinePlus