Publications by authors named "Cathryn A Broderick"

3 Publications

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Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice.

J Gene Med 2009 Jun;11(6):486-97

Division of Molecular Therapy, UCL Institute of Ophthalmology, London, UK.

Background: Adeno-associated virus serotype 2 (AAV2) vectors show considerable promise for ocular gene transfer. However, one potential barrier to efficacious long-term therapy is the development of immune responses against the vector or transgene product.

Methods: We evaluated cellular and humoral responses in mice following both single and repeated subretinal administration of AAV2, and examined their effects on RPE65 and green fluorescent protein transgene expression.

Results: Following subretinal administration of vector, splenocytes and T-cells from draining lymph nodes showed minimal activation following stimulation by co-culture with AAV2. Neutralizing antibodies (NAbs) were not detected in the ocular fluids of any mice receiving AAV2 or in the serum of mice receiving a lower dose. NAbs were present in the serum of a proportion of mice receiving a higher dose of the vector. Furthermore, no differences in immunoglobulin titre in serum or ocular fluids against RPE65 protein or AAV2 capsid between treated and control mice were detected. Histological examination showed no evidence of retinal toxicity or leukocyte infiltration compared to uninjected eyes. Repeat administration of low-dose AAV.hRPE65.hRPE65 to both eyes of RPE65(-/-) mice resulted in transgene expression and functional rescue, but re-administration of high-dose AAV2 resulted in boosted NAb titres and variable transgene expression in the second injected eye.

Conclusions: These data, which were obtained in mice, suggest that, following subretinal injection, immune responses to AAV2 are dose-dependent. Low-dose AAV2 is well tolerated in the eye, with minimal immune responses, and transgene expression after repeat administration of vector is achievable. Higher doses lead to the expression of NAbs that reduce the efficacy of repeated vector administration.
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http://dx.doi.org/10.1002/jgm.1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841821PMC
June 2009

Corrigendum to "Local Administration of an Adeno-Associated Viral Vector Expressing IL-10 Reduces Monocyte Infiltration and Subsequent Photoreceptor Damage During Experimental Autoimmune Uveitis".

Mol Ther 2006 Apr 3;13(4):829. Epub 2005 Nov 3.

Division of Molecular Therapy, Institute of Ophthalmology, University College, London, 11-43 Bath Street, London EC1V 9EL, UK; Molecular Immunology Unit, Institute of Child Health, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2005.09.013DOI Listing
April 2006

Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis.

Mol Ther 2005 Aug;12(2):369-73

Division of Molecular Therapy, Institute of Ophthalmology, University College, London, 11-43 Bath Street, London EC1V 9EL, UK.

Autoimmune posterior uveitis is a chronic, potentially blinding inflammatory disease of the eye. It is commonly treated with immunosuppressive drugs that have adverse long-term effects. Advances in gene transfer techniques have enabled long-term, stable transduction of retinal cells following subretinal injection with adeno-associated viral (AAV) vectors. Here we report for the first time that subretinal injection of rAAV-2 encoding murine IL-10 into the retina of C57BL/6 mice significantly decreases the median experimental autoimmune uveitis (EAU) disease severity. This protection is shown to be due to a decrease in the number and activation status of infiltrating monocytes during EAU, as determined by costimulatory molecule expression and nitrotyrosine detection. No differences within splenocyte proliferative responses or serum antibody levels were detected, emphasizing the potential of gene therapy strategies in ameliorating autoimmune responses in local microenvironments without unwanted systemic effects.
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http://dx.doi.org/10.1016/j.ymthe.2005.03.018DOI Listing
August 2005