Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK.
Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes.
Nat Biotechnol. 2009 Jan;27(1):59-65.
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The results reported by K.D. Foust et al. are of great interest for a number of reasons.
They provide evidence for a surprising transduction pattern in the central nervous system (CNS) following intravenous administration of recombinant AAV9. In newborn mice, transduction of long-projection neurons following intravenous injection presents an overall pattern similar to what has previously been observed for other AAV serotypes such as AAV6 (1). However, the rate of transduction reaches unprecedented efficacy, with about 60 percent of motor neurons transduced. Even more surprising is the dramatic change in the transduction pattern observed following a similar procedure in adult mice, with a predominant targeting of astrocytes. This is at odds with the tropism of most AAV vectors, which has proved mostly neuronal so far. When injected directly into the brain parenchyma, the recombinant AAV9 used in this study displays the expected neuronal pattern of infection. Thus, rather than reflecting a peculiar tropism of the serotype 9, astrocytic transduction seems to be due to a combination of specific conditions including the intravenous route of administration and the adult stage of the recipient mice.
Until now, most strategies based on peripheral injection of viral vectors have been based on retrograde transport along axonal processes to enter the CNS. Quite remarkably, recombinant AAV9 appears capable of crossing the blood-brain barrier (BBB), which is usually not permeable to viral particles. Within the CNS, astrocytes may plausibly be the primary cell type exposed to viral particles. Nevertheless, it is important to find out by which mechanism the virus is capable of crossing the BBB, in order to determine whether that particular virus can be safely employed in these conditions, and whether this feature could be conferred to other types of viral vectors.
Genetic modification of astrocytes via the peripheral injection of a viral vector opens new avenues for manipulation of glial cells, whose role appears increasingly important in a number of neurodegenerative diseases. In amyotrophic lateral sclerosis, such a flexible technique may be crucial to decipher the interplay among astrocytes, neurons, and possibly also microglia leading to the demise of neuromuscular connections (2). However, before considering any therapeutic application, it will be essential to assess the robustness of this transduction pattern across rodent disease models and various methods of vector preparation. For instance, it is unclear whether the use of self-complementary AAV vectors constitutes an important factor (3). Most importantly, it remains unknown how this approach can be scaled up to large mammalian species such as primates, and whether the virus doses needed are compatible with clinical applications.
Towne C, Raoul C, Schneider BL, Aebischer P.
Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice.
Mol Ther. 2008 Jun;16(6):1018-25. Epub 2008 Apr 15
Boillée S, Vande Velde C, Cleveland DW.
ALS: a disease of motor neurons and their nonneuronal neighbors.
Neuron. 2006 Oct 5;52(1):39-59.
Hollis ER, Kadoya K, Hirsch M, Samulski RJ, Tuszynski MH.
Efficient retrograde neuronal transduction utilizing self-complementary AAV1.
Mol Ther. 2008 Feb;16(2):296-301.