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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

GAA activity. (a) Serum. (b) Serum by sex. Differences indicated between male and female mice indicated (two-tailed t-test). GAA activity on study day (SD) 15 for (c)male and (d) female mice in each group. GAA on SD 113 for (e) male and (f) female in each group. Mean ± SD is shown. #P = 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001. Group number indicated on the horizontal axes. Group: 1, vehicle; 2, vector; 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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fig2: GAA activity. (a) Serum. (b) Serum by sex. Differences indicated between male and female mice indicated (two-tailed t-test). GAA activity on study day (SD) 15 for (c)male and (d) female mice in each group. GAA on SD 113 for (e) male and (f) female in each group. Mean ± SD is shown. #P = 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001. Group number indicated on the horizontal axes. Group: 1, vehicle; 2, vector; 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: GAA activity was elevated in the serum of GAA-KO mice following vector administration (Figure 2a; groups 4, 5 and 8), in comparison with the administration of vehicle (group 3). GAA activity was also detected in vehicle-treated serum, consistent with a prior report.6 A sex-determined response was detected, when serum GAA activity was significantly elevated in male, vector-treated mice in comparison with female mice (Figure 2b; groups 2, 4, 5, 7 and 8). The serum GAA was significantly elevated in male mice from vector-treated groups, in comparison with female mice (Figure 2b; groups 4, 5, 7, and 8). GAA activity was slightly, but significantly elevated in male vehicle-treated mice, in comparison to female mice without explanation (Figure 2b; group 3). However, the much higher elevations of GAA activity in vector-treated groups of male mice were attributable to GAA expression from the vector.


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)

GAA activity. (a) Serum. (b) Serum by sex. Differences indicated between male and female mice indicated (two-tailed t-test). GAA activity on study day (SD) 15 for (c)male and (d) female mice in each group. GAA on SD 113 for (e) male and (f) female in each group. Mean ± SD is shown. #P = 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001. Group number indicated on the horizontal axes. Group: 1, vehicle; 2, vector; 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

fig2: GAA activity. (a) Serum. (b) Serum by sex. Differences indicated between male and female mice indicated (two-tailed t-test). GAA activity on study day (SD) 15 for (c)male and (d) female mice in each group. GAA on SD 113 for (e) male and (f) female in each group. Mean ± SD is shown. #P = 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001. Group number indicated on the horizontal axes. Group: 1, vehicle; 2, vector; 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: GAA activity was elevated in the serum of GAA-KO mice following vector administration (Figure 2a; groups 4, 5 and 8), in comparison with the administration of vehicle (group 3). GAA activity was also detected in vehicle-treated serum, consistent with a prior report.6 A sex-determined response was detected, when serum GAA activity was significantly elevated in male, vector-treated mice in comparison with female mice (Figure 2b; groups 2, 4, 5, 7 and 8). The serum GAA was significantly elevated in male mice from vector-treated groups, in comparison with female mice (Figure 2b; groups 4, 5, 7, and 8). GAA activity was slightly, but significantly elevated in male vehicle-treated mice, in comparison to female mice without explanation (Figure 2b; group 3). However, the much higher elevations of GAA activity in vector-treated groups of male mice were attributable to GAA expression from the vector.

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