Gilkes J A, Bloom M D, Heldermon C D
Department of Medicine, University of Florida, Gainesville, FL, USA.
Mol Genet Metab Rep. 2015 Dec 7;6:48-54. doi: 10.1016/j.ymgmr.2015.11.006. eCollection 2016 Mar.
Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease caused by a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. Since early therapeutic intervention is likely to yield the most efficacious results, we sought to determine the possible therapeutic utility of rAAV in early gene therapy based interventions. Currently, the application of recombinant adeno-associated virus (AAV) vectors is one of the most widely used gene transfer systems, and represents a promising approach in the treatment of MPS IIIB. From a translational standpoint, a minimally invasive, yet highly efficient method of vector administration is ideal. The thalamus is thought to be the switchboard for signal relay in the central nervous system (CNS) and therefore represents an attractive target. To identify an optimal AAV vector for early therapeutic intervention, and establish whether thalamic administration represents a feasible therapeutic approach, we performed a comprehensive assessment of transduction and biodistribution profiles of four green fluorescent protein (GFP) bearing rAAV serotypes, -5, -8, -9 and -rh10, administered bilaterally into the thalamus. Of the four serotypes compared, AAV8 and -9 proved superior to AAV5 and -rh10 both in biodistribution and transduction efficiency profiles. Genotype differences in transduction efficiency and biodistribution patterns were also observed. Importantly, we conclude that AAV8 and to a lesser extent, AAV9 represent preferable candidates for early gene therapy based intervention in the treatment of MPS IIIB. We also highlight the feasibility of thalamic rAAV administration, and conclude that this method results in moderate rAAV biodistribution with limited treatment capacity, thus suggesting a need for alternate methods of vector delivery.
B型Sanfilippo综合征（MPS IIIB）是一种溶酶体贮积病，由N - 乙酰 - 氨基葡萄糖苷酶（NAGLU）活性缺乏引起。由于早期治疗干预可能产生最有效的结果，我们试图确定重组腺相关病毒（rAAV）在基于早期基因治疗的干预措施中的潜在治疗效用。目前，重组腺相关病毒（AAV）载体的应用是最广泛使用的基因转移系统之一，是治疗MPS IIIB的一种有前景的方法。从转化医学的角度来看，一种微创但高效的载体给药方法是理想的。丘脑被认为是中枢神经系统（CNS）中信号中继的总机，因此是一个有吸引力的靶点。为了确定用于早期治疗干预的最佳AAV载体，并确定丘脑给药是否代表一种可行的治疗方法，我们对四种携带绿色荧光蛋白（GFP）的rAAV血清型 -5、 -8、 -9和 -rh10双侧注入丘脑后的转导和生物分布情况进行了全面评估。在比较的四种血清型中，AAV8和 -9在生物分布和转导效率方面均优于AAV5和 -rh10。还观察到转导效率和生物分布模式的基因型差异。重要的是，我们得出结论，AAV8以及在较小程度上AAV9是基于早期基因治疗干预治疗MPS IIIB的更优候选者。我们还强调了丘脑rAAV给药的可行性，并得出结论，这种方法导致rAAV生物分布适中但治疗能力有限，因此表明需要替代的载体递送方法。
