6 results on '"Mcintosh, Jenny"'
Search Results
2. 490. Successful Readministration of AAV8 Following Administration of Nondepleting CD4 Antibody at the Time of Vector Administration.
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McIntosh, Jenny H., Cochrane, Melanie, Prizzey, Arnold, Waldmann, Herman, Davidoff, Andrew M., and Nathwani, Amit C.
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CD4 antigen , *GENETIC transformation , *GENOMES , *LIVER cells , *IMMUNOSUPPRESSIVE agents , *TRANSGENE expression - Abstract
Transgene expression from the liver following recombinant adeno-associated viral vector (rAAV) gene transfer is mediated mainly by episomally maintained genomes. For chronic disorders such as haemophilia this raises concerns that transgene expression will decline to subtherapeutic levels over time with the natural turnover of hepatocytes in humans. Neutralising antibodies that develop at the time of primary vector administration will however prevent readministration of the same serotype. Therefore strategies that allow repeated administration of the optimal vector system may be required to maintain transgene expression at therapeutic levels. We have used a non-depleting CD4 antibody (NDCD4) in conjunction with other immunosuppressive agents in an attempt to attenuate the primary immune response to AAV. Cohorts of male C57BL/6 mice (n= 7-8) were treated with NDCD4 (0.5mg/mouse) alone, or in combination with cyclosporine (CyA) 25mg/kg or mycophenolate mofetil (MMF) 20mg/kg on days −1, 0, +1, 3, 6, 8 after tail vein administration of a pseudotype 8 vector encoding human factor IX. Additional cohorts received CyA or MMF alone and one group received no treatment. CD4 T lymphocyte analysis by FACs with an antibody against CD4 epitope B over 56 days, showed a moderate decline in the NDCD4 treated cohorts (34%) compared to naïve mice (sham treated). At day 98 anti-AAV8 antibody titers were reduced in cohorts receiving NDCD4 alone (11.3±3.5) or in combination with MMF (12.3±5.5). However, the humoral response in CyA+NDCD4 was undetectable. Secondary challenge with a low titer (5×1010) of AAV8 encoding human β interferon (hβIFN) resulted in serum hβIFN levels of 7.3±3.9 ng/mL in the CyA+NDCD4 cohort. These levels were comparable (9.0±5.2 ng/mL) to those in animals receiving only AAV8 hβIFN. Hence treatment with NDCD4 antibody and cyclosporine at the time of vector administration can substantially attenuate the immune response to primary immunisation with AAV, enabling repeat administration and efficient transduction with vectors based on the same serotype. Unlike previously used strategies our approach offers significant safety advances and will have widespread appeal.Molecular Therapy (2006) 13, S190–S190; doi: 10.1016/j.ymthe.2006.08.560 [ABSTRACT FROM AUTHOR]
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- 2006
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3. Long-term Safety and Efficacy Following Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 5 and 8 Capsid Proteins.
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Nathwani, Amit C, Rosales, Cecilia, McIntosh, Jenny, Rastegarlari, Ghasem, Nathwani, Devhrut, Raj, Deepak, Nawathe, Sushmita, Waddington, Simon N, Bronson, Roderick, Jackson, Scott, Donahue, Robert E, High, Katherine A, Mingozzi, Federico, Ng, Catherine YC, Zhou, Junfang, Spence, Yunyu, McCarville, M Beth, Valentine, Marc, Allay, James, and Coleman, John
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DISEASE vectors , *GENE therapy , *TRANSGENE expression , *LIVER cells , *LABORATORY monkeys , *SEROTYPING - Abstract
Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 1012 pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 1011 pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients. [ABSTRACT FROM AUTHOR]
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- 2011
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4. Stable Human FIX Expression After 0.9G Intrauterine Gene Transfer of Self-complementary Adeno-associated Viral Vector 5 and 8 in Macaques.
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Mattar, Citra NZ, Nathwani, Amit C, Waddington, Simon N, Dighe, Niraja, Kaeppel, Christine, Nowrouzi, Ali, Mcintosh, Jenny, Johana, Nuryanti B, Ogden, Bryan, Fisk, Nicholas M, Davidoff, Andrew M, David, Anna, Peebles, Donald, Valentine, Marcus B, Appelt, Jens-Uwe, von Kalle, Christof, Schmidt, Manfred, Biswas, Arijit, Choolani, Mahesh, and Chan, Jerry KY
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GENETIC transformation , *MICROBIAL genetics , *BACTERIOPHAGES , *CERCOPITHECIDAE , *IMMUNOLOGY - Abstract
Intrauterine gene transfer (IUGT) offers ontological advantages including immune naiveté mediating tolerance to the vector and transgenic products, and effecting a cure before development of irreversible pathology. Despite proof-of-principle in rodent models, expression efficacy with a therapeutic transgene has yet to be demonstrated in a preclinical nonhuman primate (NHP) model. We aimed to determine the efficacy of human Factor IX (hFIX) expression after adeno-associated-viral (AAV)-mediated IUGT in NHP. We injected 1.0-1.95 × 1013 vector genomes (vg)/kg of self-complementary (sc) AAV5 and 8 with a LP1-driven hFIX transgene intravenously in 0.9G late gestation NHP fetuses, leading to widespread transduction with liver tropism. Liver-specific hFIX expression was stably maintained between 8 and 112% of normal activity in injected offspring followed up for 2-22 months. AAV8 induced higher hFIX expression (P = 0.005) and milder immune response than AAV5. Random hepatocellular integration was found with no hotspots. Transplacental spread led to low-level maternal tissue transduction, without evidence of immunotoxicity or germline transduction in maternal oocytes. A single intravenous injection of scAAV-LP1-hFIXco to NHP fetuses in late-gestation produced sustained clinically-relevant levels of hFIX with liver-specific expression and a non-neutralizing immune response. These data are encouraging for conditions where gene transfer has the potential to avert perinatal death and long-term irreversible sequelae. [ABSTRACT FROM AUTHOR]
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- 2011
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5. Preliminary evaluation of a self-complementary AAV2/8 vector for hepatic gene transfer of human apoE3 to inhibit atherosclerotic lesion development in apoE-deficient mice
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Osman, Eyman, Evans, Vanessa, Graham, Ian R., Athanasopoulos, Takis, McIntosh, Jenny, Nathwani, Amit C., Simons, J. Paul, Dickson, George, and Owen, James S.
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GENETIC transformation , *APOLIPOPROTEIN E , *ATHEROSCLEROSIS , *LABORATORY mice , *HYPERCHOLESTEREMIA , *DRUG efficacy , *RECOMBINANT viruses - Abstract
Abstract: Hepatic gene transfer of atheroprotective human apoE by recombinant viral vectors can reverse hypercholesterolaemia and inhibit atherogenesis in apoE-deficient (apoE−/−) mice. Here, in preliminary studies we assess the effectiveness of a recently developed self-complementary adeno-associated virus (scAAV) serotype 8 vector, driven by a hepatocyte-specific promoter (LP1), for liver-directed gene delivery of human apoE3. Vector viability was validated by transducing cultured HepG2 cells and measuring secretion of apoE3 protein. Male and female apoE−/− mice, 6-month old and fed on normal chow, were intravenously injected with 1×1011 vg (vector genomes) of scAAV2/8.LP1.apoE3; age-matched untreated mice served as controls. In male mice, plasma apoE3 levels were sufficiently high (up to 17μg/ml) to normalize plasma total cholesterol and ameliorate their proatherogenic lipoprotein profile, by reducing VLDL/LDL and increasing HDL 5-fold. At termination (12 weeks) development of aortic atherosclerosis was significantly retarded by 58% (aortic lesion area 8.2±1.4% vs. 19.3±2.4% in control males; P <0.001). Qualitatively similar anti-atherogenic effects were noted when female mice were treated, but the benefits were less marked and aortic lesions, for example, were reduced by only 33% (15.7±3.7% vs. 23.6±6.9%). Although group numbers were small (n =4/5), this gender-specific difference reflected two to three times less apoE3 in plasma of female mice at weeks 3 and 6, implying that gene transfer to female liver using scAAV vectors may require additional optimization, despite their established superior potency to conventional single-stranded (ssAAV) vectors. [Copyright &y& Elsevier]
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- 2009
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6. 711. Treatment of Acute Myeloid Leukemia by rAAV 8 Vector Mediated Human Interferon-β Gene Transfer
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Benjamin, Reuben, Davidoff, Andrew M., Arnold, Pizzey, Singh, Nalini, Khwaja, Asim, McIntosh, Jenny, Ng, Cathy C.Y., Meager, Tony, Wadhwa, Meenu, and Nathwani, Amit C.
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ACUTE myeloid leukemia treatment , *INTERFERONS - Abstract
An abstract of the article "Treatment of Acute Myeloid Leukemia by rAAV 8 Vector Mediated Human Interferon-β Gene Transfer," by Reuben Benjamin,1 Andrew M. Davidoff, Nalini Singh, Asim Khwaja, Jenny McIntosh, Cathy C. Y. Ng, Tony Meager, Meenu Wadhwa and Amit C. Nathwani is presented.
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- 2005
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