Gray, AL;
O'Leary, C;
Liao, A;
Agundez, L;
Youshani, AS;
Gleitz, HF;
Parker, H;
... Bigger, B; + view all
(2019)
An improved AAV vector for neurological correction of the mouse model of Mucopolysaccharidosis IIIA.
Human Gene Therapy
, 30
(9)
pp. 1052-1066.
10.1089/hum.2018.189.
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Agundez_An improved AAV vector for neurological correction of the mouse model of Mucopolysaccharidosis IIIA_AAM.pdf - Accepted Version Download (2MB) | Preview |
Abstract
Patients with the lysosomal storage disease mucopolysaccharidosis IIIA (MPSIIIA) lack the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), one of the many enzymes involved in degradation of heparan sulphate. Build-up of undegraded heparan sulphate results in severe progressive neurodegeneration for which there is currently no treatment. Experimental gene therapies based on gene addition are currently being explored. Following pre-clinical evaluation in MPSIIIA mice, an AAVrh10 vector designed to deliver SGSH and sulfatase modifying factor 1 (SAF301) was trialled in four MPSIIIA patients showing good tolerance and absence of adverse events with some improvements in neurocognitive measures. Here we aimed to further improve SAF301 by removing sulfatase modifying factor 1 (SUMF1) and assess if expression of this gene is needed to increase the SGSH enzyme activity (SAF301b). Secondly, we exchanged the murine phosphoglycerate kinase (PGK) promotor with a chicken beta actin/CMV composite (CAG) promotor (SAF302) to see if we could further boost SGSH expression levels. The three different vectors were administered to MPSIIIA mice via intracranial injection and SGSH expression levels were compared 4 -weeks post-treatment. Removal of SUMF1 resulted in marginal reductions in enzyme activity. However, promotor exchange significantly increased the amount of SGSH expressed in the brain leading to superior therapeutic correction with SAF302. Biodistribution of SAF302 was further assessed using GFP (SAF302GFP), indicating that vector spread was limited to the area around the injection tract. Further modification of the injection strategy to a single depth with higher injection volume increased vector distribution leading to more widespread GFP distribution and sustained expression, suggesting this approach should be adopted in future trials.
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