Absence of an intrathecal immune reaction to a helper-dependent adenoviral vector delivered into the cerebrospinal fluid of non-human primates

Abstract

Inflammation and immune reaction, or pre-existing immunity towards commonly used viral vectors for gene therapy severely impair long-term gene expression in the central nervous system (CNS), impeding the possibility to repeat the therapeutic intervention. Here, we show that injection of a helper-dependent adenoviral (HD-Ad) vector by lumbar puncture into the cerebrospinal fluid (CSF) of non-human primates allows long-term (three months) infection of neuroepithelial cells, also in monkeys bearing a pre-existing anti-adenoviral immunity. Intrathecal injection of the HD-Ad vector was not associated with any sign of systemic or local toxicity, nor by signs of a CNS-specific immune reaction towards the HD-Ad vector. Injection of HD-Ad vectors into the CSF circulation may thus represent a valuable approach for CNS gene therapy allowing for long-term expression and re-administration.

DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice

“…administration, i.t. injection of HDAd has previously been reported to invoke neither systemic or local toxicity nor a CNS-specific immune reaction (42). The low toxicity found in the present study may be, at least in part, due to the presence of few immune cells in CSF.…”

“…It has previously been reported that the immune response to foreign material injected i.t. is attenuated (18,42), which may allow for the repeat administration of HDAd via this route for repeated treatments. We note that HDAd can be administered repeatedly even when it is given by the i.v.…”

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

“…48 Recently, interesting results for central nervous system gene therapy have been generated by delivering HDAd into the cerebrospinal fluid by lumbar puncture in nonhuman primates. 49 These studies showed that HDAd given by this route of administration result in long-term (at least 3 months) transgene expression without systemic or local toxicity in animals with pre-existing antiadenoviral immunity.…”

Adenoviral Vectors: Potential and Challenges as a Gene Delivery System

“…Due to the chronic nature of neurodegenerative diseases, it is of particular interest whether the treatment can be offered over a long period of time. HD-AdV vectors have been administered into the cerebrospinal fluid (CSF) of non-human primates through lumbar puncture, and it was shown that the intervention allowed a long-lasting (three months) infection of the neuroepithelial cells without any systemic or local toxicity (Butti et al, 2008).…”

“…Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis that has been adopted for pre-clinical studies. HD-AdV vectors expressing IL-4 were administered into the CSF of immunocompetent mice that allowed transduction of neuroepithelial cells and prolonged (five months) transgene expression without any adverse effects (Butti et al, 2008).…”