Technology

Neurodegenerative diseases (NDD) are a group of disorders of the central nervous system (CNS) that cause progressive death of nerve cells and loss of function in the brain and spinal cord. The CNS compartments are represented by the parenchyma of the brain and spinal cord, including the intracellular space with the intracellular fluids (ICF) and the extracellular space with the interstitial fluid (ISF), and the cerebrospinal fluid (CSF) space.

The spinal CSF fluctuates in biphasic tides of cephalic ebb and caudal flow. The fluid dynamics of CSF fluctuation in the spinal SAS are complex. NEUROSTECH is harnessing the power of CSF dynamics to develop ground-breaking new medical devices.

Delivering drugs to the CNS is challenging due to limited penetration through the Blood-Brain Barrier (BBB). Small molecule diffusion across the BBB resembles solute-free diffusion in membranes. A molecule’s BBB permeability depends on molecular weight (MW) and structure. Molecules with MW > 450 Daltons or those forming >7 hydrogen bonds face low permeability unless assisted by carrier-mediated transport. Conversely, molecules with MW < 450 Daltons and ≤7 hydrogen bonds may cross the BBB effectively, barring active efflux transporter interference.

Pathological conditions like stroke or cancer cause structural and functional BBB damage, increasing immune cell infiltration and substance passage. BBB can be opened using hyperosmotic infusions or focused ultrasounds, facilitating drug entry, including monoclonal antibodies (mAbs). Neurodegenerative diseases (NDDs), linked to chronic inflammation, oxidative stress, and misfolded protein buildup, worsen BBB dysfunction and reduce drug delivery. Similar changes in the Blood-Cerebrospinal Fluid Barrier (BCSFB) also affect permeability in NDDs.

Intrathecal pumps exemplify implantable CNS drug delivery systems. These devices use an electromechanical pump housed in a metal reservoir and a catheter implanted in the spinal intrathecal space to deliver medication directly to cerebrospinal fluid (CSF). Pumps are available in constant-rate and programmable models, enabling precise drug release and low-dose efficacy, which helps minimize adverse effects. However, they are not without risks. Complications such as pump malfunction, CSF leaks, granulomas, flow obstructions, infections, or overdose from incorrect programming may arise. Addressing these challenges requires ongoing monitoring, proper device maintenance, and advancements in pump design to improve safety and efficacy.

Different approaches have been investigated with the aim of removing pathogenic proteins from the CNS, including inhibition of protein synthesis, and promoting protein degradation. Most therapeutic strategies addressed to enhance the clearance of brain proteins rely on clearing them from the periphery. Disease-modifying therapies, such as monoclonal antibodies (mAb) against target molecules, have recently showed clinical benefits in NDD.

However, safety remains a concern, since peripherally administered mAbs may lead to serious side effects, such as immunologically mediated amyloid-related imaging abnormalities (ARIA) after anti-Aß mAb therapies. However, there might be a much more direct way of clearing proteins from the brain than removing them from the plasma: removing them from the CSF (more info here, here and here).

This is the rationale of the so-called “CSF-sink therapeutic hypothesis”

The figure above represents target molecule dynamics in four scenarios.

From left to right:

1. physiological condition (healthy subject).
2. pathological condition (untreated neurodegenerative disease).
3. pathological condition treated with peripheral sink therapeutic
4. pathological condition treated with CSF-sink therapeutic approach.

Arrows indication:

• Red arrows represent spontaneous equilibrium of target molecules between CNS fluid compartments
• Green arrows represent pathways of therapeutic clearance of target molecules
• Orange arrows represent the secondary equilibrium of target molecules between CNS fluid compartments after therapy.

Indeed, several attempts have been made to treat neurodegenerative diseases using different CSF filtration systems. For example, in Amyotrophic Lateral Sclerosis (ALS), extracorporeal CSF filtration was shown to successfully mitigate the neurotoxic capacity of CSF from subjects with sporadic ALS in vitro and in a mouse model.

However, a very small randomized, controlled, and open study in the 1990s, concluded that filtration of 200–250 mL CSF daily, over five days, did not seem to have a substantial therapeutic effect in patients with ALS. In a single case of familial ALS, there was subjective, but no but no objective, improvement of the patient immediately after CSF filtration and two weeks later.

Therapeutics such as enzymes and antibodies, which are mostly intended to bind molecular targets for clearance from the organism, do not really need to be released in the fluid or tissue to action. In fact, binding to the molecular target can be achieved regardless of the compartment.

NEUROSTECH proprietary intrathecal (IT) pseudo-delivery is a novel concept to administer drugs to treat devastating CNS conditions relying on the CSF-sink therapeutic strategy, by a fully implantable drug delivery system (DDS) to place the therapeutic drug (like mAbs) in close contact with molecular targets inside of the device, without delivering it to the biological fluid (thus “pseudo”-delivery).

INVERLEASE is the first DDS controlled at the nanometric scale, and endowed with nanoporous membranes acting on the CNS [see also here and here]. INVERLEASE look similar to intrathecal pumps as they also have a subcutaneous reservoir and an intrathecal catheter providing access to the CSF.

However, they are not endowed with electromechanical pumps. Target molecules are delivered inside the system at the right time in the right place, thus being trapped or cleaved and eliminated from the CNS. Drugs are not released from the reservoir to the organism, and they can be replaced as needed percutaneously through self-sealing septa in the reservoir.

Our advanced proprietary technology is an significant advanced over the state of the art, consisting on:

1. Smart catheters: our understanding of CSF flow dynamics allows us to design the next generation of intrathecal catheters powering pumpless devices
2. Tailored nanoporous membranes: our precise control of nanoporous membranes enables us to gain full control of selective molecular permeability
3. Subcutaneous reservoirs: We develop a third generation of subcutaneous reservoirs with advanced architecture and convenient percutaneous ports. First generation systems consisted in passive implantable Ommaya reservoirs, the second generation used electromechanical pumps to force flow (Medtronic pumps) and the third generation takes advantage of pumpless fluid flow to enable the INVERLEASE