Assessing the pharmacokinetics of large molecules in the CNS

‘There are some interesting new treatment approaches in neurology that involve the administration of large molecules, such as antibodies and ASOs,’ says Dr Philip Kremer, Research Director in Neurology. However, how such antibodies pass from the blood or cerebrospinal fluid (CSF) to the interstitial fluid around brain cells and into brain cells themselves is still only partially known. ‘At CHDR, we live by our philosophy of question-based drug development. The first question in developing a new drug should always be: does the compound reach the target? The answer to that question is often more complex — and more enlightening — than it might seem.’

Reaching the target

Unlike classical small molecules, antibodies and nucleotides do not reach the brain easily after intravenous administration. The first big hurdle they have to overcome is the blood-brain barrier. To achieve this, some antibodies — for example, those being developed as a possible treatment for Alzheimer’s disease — are administered in very high concentrations, of which a mere 0.1~0.2% pass into the CSF.

Meanwhile, ASOs and some other large molecules are administered intrathecally, bypassing the blood-brain barrier. But they still have to make the long journey from the cauda equina at the base of the spinal cord to their target areas in the brain. Kremer: ‘Monkeys like macaques are often considered to be a reliable preclinical model for this approach. But macaques are much smaller than humans. As the oligonucleotide has to travel to its target area via diffusion, physical distance is an important factor.’

Vibrating vest

There are several possible ways to try and accelerate the transport of large molecules through the space containing the CSF. One promising approach is a vibrating vest, which causes fluctuations in pressure that set the CSF in motion. However, this fluctuating pressure on the CSF may also lead to increased leakage of the compound through nerve roots. To assess the amount of leakage, Kremer and his team will start by focusing on naturally occurring proteins, such as tau protein.

‘We’ll measure the concentration of these proteins in the CSF and in the blood while the study participant is at rest. Then we’ll ask the participant to put on the vibrating vest and see if those concentrations change,’ says Kremer. ‘Assuming that the production of proteins remains constant, this way we can see if there are shifts between the two compartments, indicating leakage.’

Imaging techniques

To track the fate of large molecules that are administered intrathecally, the team plans to use imaging. ‘We could, for example, use a gadolinium-based contrast agent to make the compound visible to MRI. Or we could use radioactive tracers and PET scanning. In any case, the aim is to find out how these molecules move through the CSF,’ says Kremer. ‘This is exploratory research, but with clear practical implications. By gaining an understanding of the kinetics of such molecules within the CNS, we can contribute to the development of these exciting new therapeutic approaches.’