Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I

Abstract

Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.

Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

“…Whether or not placing the subject in the Trendelenburg position right after infusion can potentiate the efficacy of brain transduction by this procedure remains debated (Meyer et al, 2015). Intranasal Delivery for Brain Transduction While the primary indication for intranasal AAV delivery has been to target the respiratory tract, this non-invasive gene transfer strategy has also been recently applied for the treatment of MPS I (Belur et al, 2017) (Figure 2). Adult IDUA-deficient mice were instilled intranasally with an AAV9.IDUA, and a complete restoration of enzyme activity to normal levels was noticed 5 months post treatment in all parts of the brain, even though the area of AAV transduction remained localized to the olfactory bulb.…”

Possible strategies to cross the blood–brain barrier

“…Lipid-based NPs have been studied for intranasal drug delivery and this non-invasive strategy approach has been used to assess the efficacy of treatment of neurological manifestation in MPS I disease. Laboratory experiments in mice showed that intranasal administration of an α- l -iduronidase (IDUA) encoding adeno-associated virus serotype 9 (AAV9) vector results in enzyme diffusion into deeper areas of the brain and related reduction of tissue GAG storage materials in the brain [ 39 ]. Intranasal delivery could then potentially be used to treat CNS manifestations of MPS I.…”

Cognitive Abilities of Dogs with Mucopolysaccharidosis I: Learning and Memory

“…However, because the objects used in this test had a very different shape, the latter will be considered as the primary distinctive factor in this report. The delayed non-match to position (DNMP) task evaluates working-and visuospatial memory and has been previously described in the literature [28,29,57]. One trial consists of a sample phase, a progressive time delay interval (20-, 30-, 40-, 50-, or 60-s), followed by a non-match phase ( Figure 2).…”

“…Cognition tests of human MPS I patients reflect impaired working memory [26] which may be due to smaller hippocampal volumes [27]. Furthermore, MPS I affected mice show deficits in learning and navigation [28,29], impaired long-term memory and reduced rearing behavior [30]. Despite reports of behavioral and cognitive differences in MPS I affected mice [31] and humans [26], very little has been described in dogs.…”