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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

Growth and feeding. (a) Body weights for each experimental group by sex. Each bar represents the mean value of group body weight (n = 10 except that n = 9 for group 8 males and n = 7 for group 8 females). (b) Weekly food consumption by sex for mice euthanized at study day (SD) 15; b, groups 3–8 animals were euthanized at SD 113, and showed no difference for food consumption between groups (data not shown). (c) Blood chemistry testing. Units are as follows, for sodium (mmol/l), alkaline phosphatase (U/l), and cholesterol (mg/dl). Mean ± SD is shown; *P < 0.05. 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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fig1: Growth and feeding. (a) Body weights for each experimental group by sex. Each bar represents the mean value of group body weight (n = 10 except that n = 9 for group 8 males and n = 7 for group 8 females). (b) Weekly food consumption by sex for mice euthanized at study day (SD) 15; b, groups 3–8 animals were euthanized at SD 113, and showed no difference for food consumption between groups (data not shown). (c) Blood chemistry testing. Units are as follows, for sodium (mmol/l), alkaline phosphatase (U/l), and cholesterol (mg/dl). Mean ± SD is shown; *P < 0.05. 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: The AAV2/8-LSPhGAApA vector (1.6 × 1013 vp/kg), either alone or in combination with ERT, did not affect the body weights of mice as compared to their respective control group at the same SD time point (Figure 1a). The weekly measurement of food consumption did not reveal any significant reduction of appetite in animals administered vector, ERT, or vector plus ERT, compared with control animals (Figure 1b). No gross pathological lesions were attributable to vector administration, and only minor sporadic anomalies were identified upon postmortem examination.


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)

Growth and feeding. (a) Body weights for each experimental group by sex. Each bar represents the mean value of group body weight (n = 10 except that n = 9 for group 8 males and n = 7 for group 8 females). (b) Weekly food consumption by sex for mice euthanized at study day (SD) 15; b, groups 3–8 animals were euthanized at SD 113, and showed no difference for food consumption between groups (data not shown). (c) Blood chemistry testing. Units are as follows, for sodium (mmol/l), alkaline phosphatase (U/l), and cholesterol (mg/dl). Mean ± SD is shown; *P < 0.05. 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

fig1: Growth and feeding. (a) Body weights for each experimental group by sex. Each bar represents the mean value of group body weight (n = 10 except that n = 9 for group 8 males and n = 7 for group 8 females). (b) Weekly food consumption by sex for mice euthanized at study day (SD) 15; b, groups 3–8 animals were euthanized at SD 113, and showed no difference for food consumption between groups (data not shown). (c) Blood chemistry testing. Units are as follows, for sodium (mmol/l), alkaline phosphatase (U/l), and cholesterol (mg/dl). Mean ± SD is shown; *P < 0.05. 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: The AAV2/8-LSPhGAApA vector (1.6 × 1013 vp/kg), either alone or in combination with ERT, did not affect the body weights of mice as compared to their respective control group at the same SD time point (Figure 1a). The weekly measurement of food consumption did not reveal any significant reduction of appetite in animals administered vector, ERT, or vector plus ERT, compared with control animals (Figure 1b). No gross pathological lesions were attributable to vector administration, and only minor sporadic anomalies were identified upon postmortem examination.

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