Adeno-Associated Virus Delivery Limitations for Neurological Indications

Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease

“…Although valuable insights can be gained from in vitro and in vivo small animal studies, testing delivery carriers in models that better account for the size, complexity, and species variability of the human CNS is critical for consideration of clinical translation. 42 To this end, we evaluated the ability of C3 LNPs to deliver mRNA to the fetal brain in the NHP via ICV administration at a gestational age akin to a midgestation human fetus and demonstrated transfection of the brain ventricular lining akin to our studies in the mouse model. In addition, given the ultimate goal of developing an LNP platform for delivery into the CSF-filled ventricles of patients, we assessed the stability of C3 LNPs in human CSF and demonstrated that LNPs retained their physiochemical properties upon incubation in CSF but not human serum ex vivo.…”

“…Although valuable insights can be gained from in vitro and in vivo small animal studies, testing delivery carriers in models that better account for the size, complexity, and species variability of the human CNS is critical for consideration of clinical translation . To this end, we evaluated the ability of C3 LNPs to deliver mRNA to the fetal brain in the NHP via ICV administration at a gestational age akin to a midgestation human fetus and demonstrated transfection of the brain ventricular lining akin to our studies in the mouse model.…”

“…For instance, Waddington and colleagues utilized AAV9 to rescue a mouse model of Gaucher’s disease and demonstrated brain transduction following ICV administration of AAV9 in the fetal NHP model . While AAVs were shown to be effective for these applications, recent concern over AAV toxicity at high doses motivates the development of nonviral alternatives . This is especially important when considering fetal gene therapy or gene editing in which the fetus may be more prone to toxicities of the delivery vehicle, and the mother, who, in most cases, is unaffected by the disease, must not be harmed.…”

“…41 While AAVs were shown to be effective for these applications, recent concern over AAV toxicity at high doses motivates the development of nonviral alternatives. 42 This is especially important when considering fetal gene therapy or gene editing in which the fetus may be more prone to toxicities of the delivery vehicle, and the mother, who, in most cases, is unaffected by the disease, must not be harmed. In this study, C3 LNPs did not result in morphological changes to the fetal or neonatal murine brain parenchyma on gross examination.…”

Early distribution of18 F‐labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non‐human primates

“…In humans, the total volume of CSF is 100-400 ml, and turnover is three to five times per day. 28,29 Each minute, approximately 350 μl of the CSF is produced in the choroidal plexus and distributed into the subarachnoid space through the fourth ventricle.…”