Supraspinal gene transfer by intrathecal adeno-associated virus serotype 5

Abstract

We report the pattern of transgene expression across brain regions after intrathecal delivery of adeno-associated virus serotype 5 (AAV5). Labeling in hindbrain appeared to be primarily neuronal, and was detected in sensory nuclei of medulla, pontine nuclei, and all layers of cerebellar cortex. Expression in midbrain was minimal, and generally limited to isolated neurons and astrocytes in the cerebral peduncles. GFP immunoreactivity (-ir) in thalamus was most prominent in medial geniculate nucleus, and otherwise limited to posterior nuclei of the dorsal and lateral margins. Labeling was also observed in neurons and astrocytes of the hippocampal formation and amygdaloid complex. In the hippocampal formation, GFP-ir was found in neuronal cell bodies of the rostral ventral portion, but was largely restricted to fiber-like staining in the molecular layer of dentate gyrus and stratum lacunosum-moleculare of the rostral dorsal region. GFP-ir was seen in neurons and astroglia throughout caudal cortex, whereas in rostral regions of neocortex it was limited to isolated neurons and non-neuronal cells. Labeling was also present in olfactory bulb. These results demonstrate that intrathecal delivery of AAV5 vector leads to transgene expression in discrete CNS regions throughout the rostro-caudal extent of the neuraxis. A caudal-to-rostral gradient of decreasing GFP-ir was present in choroid plexus and Purkinje cells, suggesting that spread of virus through cerebrospinal fluid plays a role in the resulting transduction pattern. Other factors contributing to the observed expression pattern likely include variations in cell-surface receptors and inter-parenchymal space.

Adeno-associated virus 2/9 delivery of Cre recombinase in mouse primary afferents

“…In agreement with our observations, an absence or a very limited GFP distribution across the brain was previously reported following the intrathecal delivery of AAV9 and AAV8 viruses 14 , 32 . This finding however sharply contrasts other observations which reported a wide distribution of GFP in the brain 6 weeks following infection with either AAV9 or AAV5 12 , 33 .…”

Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic

“…124 Most of the studies using IT injections of various AAV serotypes have been conducted in rodents with a common outcome: the spinal cord is generally effectively transduced, but the vectors poorly reach deeper brain structures such as the striatum. [125][126][127] Therapeutic administration of AAV vectors to the CSF requires higher doses compared to local administration, and, therefore, it may be associated with a higher likelihood of causing an immune reaction. Additionally, ICV and IT deliveries have been reported to cause a vector leakage into the periphery, limiting the clinical efficacious dose in the required brain structures.…”

A bright future? Optogenetics in the periphery for pain research and therapy

“…Multiple AAV serotypes have been identified and engineered to preferentially transduce different types of neurons. AAV5, 6, 8, 9 and PHP.S have been shown to have higher tropism for dorsal root ganglion (DRG) neurons than other serotypes [16; 17; 36; 52; 53; 59; 76; 84; 98; 99; 105; 108; 119]. Moreover, it may be possible to exploit different serotypes to induce differential expression patterns within sensory neuron populations [54; 109; 111; 119].…”