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Publication Detail
Age-related seroprevalence of antibodies against AAV-LK03 in a UK population cohort.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Perocheau D, Cunningham S, Lee J, Antinao Diaz J, Waddington SN, Gilmour K, Eaglestone S, Lisowski L, Thrasher AJ, Alexander IE, Gissen P, Baruteau J
  • Publication date:
  • Journal:
    Human gene therapy
  • Medium:
  • Status:
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  • Addresses:
    Great Ormond Street Institute of Child Health, University College London, Genetics and Genomic Medicine Programme, London, United Kingdom of Great Britain and Northern Ireland.
Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. Novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials, however the prevalence of antibodies against such capsids remains largely unknown. We therefore assessed the seroprevalence of antibodies against a novel synthetic liver-tropic capsid AAV-LK03.We measured seroprevalence of IgG (i.e. neutralising and non-neutralising) antibodies and Nab to AAV-LK03 in a cohort of 323 UK patients (including 260 paediatric) and 52 juvenile rhesus macaques. We also performed comparative analysis of seroprevalence of Nab against wild-type AAV8 and AAV3B capsids.Overall IgG seroprevalence for AAV-LK03 was 39% in human samples. The titre increased with age. Prevalence of Nab was 23%, 35% and 18% for AAV-LK03, AAV3B and AAV8, respectively, with lowest seroprevalence between 3-17 years of age for all serotypes. Presence of Nab against AAV-LK03 decreased from 36% in the youngest cohort (birth-6 months) to 7% in older primary school-age children (9-11 years) and then progressively increased to 54% in late adulthood. Cross-reactivity between serotypes was >60%. Nab seroprevalence in macaques was 62%, 85% and 40% for AAV-LK03, AAV3B and AAV8, respectively.When planning for AAV gene therapy clinical trials, it is critical to know the seropositivity of the target population. In the population studied, AAV seroprevalence for AAV serotypes tested was low. However high cross-reactivity between AAV serotypes remains a barrier for re-injection. Changing of Nab seroprevalence during the first decade needs to be confirmed by longitudinal studies. This suggests that paediatric patients could respond differently to AAV therapy according to age. If late childhood would be an ideal age window, intervention at an early age when maternal Nab levels are high may be challenging. Nab positive children excluded from trials could be re-screened for eligibility at regular intervals as this status may change.
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