Abstract
BackgroundThe intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood–brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys.MethodsThere are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer 64Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer 99mTc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging.ResultsIt was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 ± 1.6 cm3.ConclusionsThese results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic.
Highlights
The intrathecal (IT) dosing route introduces drugs directly into the cerebral spinal fluid (CSF) to bypass the blood–brain bar‐ rier and gain direct access to the Central nervous system (CNS)
Magnetic Resonance Imaging (MRI) determination of CSF volume in cynomolgus monkeys To support the selection of IT dose volumes, total CSF volumes were measured in cynomolgus monkeys
We evaluated the effect of IT dose volumes ranging from ~ 3 to 20% of total monkey CSF volume determined by MRI with the amount of injected molecule kept constant within an experiment
Summary
The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood–brain bar‐ rier and gain direct access to the CNS. Several other BBB impermeable therapeutic molecules in development, including proteins, nucleic acids, viral gene therapy vectors, stem cells and exosomes are pursuing use of the IT dosing route to target diseases of the CNS. Since these approaches aim to treat various diseases in both pediatric and adult patient populations that can be associated with significant variability in intersubject anatomy and CSF volumes, common principles are needed to optimize the IT dosing procedure for broad neuraxial delivery. Approaches that increase neuraxial drug exposure after lumbar IT delivery will be useful as ASO therapies, and other intrathecally delivered modalities, advance into indications that involve more rostral brain structures
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