Low pulsed electrical fields for inducing transient BBB disruption (#2017041)

The Need

The blood brain barrier (BBB) is a multicellular vascular structure that separates the central nervous system (CNS) from peripheral blood circulation. The BBB acts as a physical barrier limiting passage of molecules and cells from the blood to brain tissues, thus keeping out toxins that may damage neuronal function. Nevertheless, exactly for this reason, the BBB forms a major obstacle for drug penetration into the brain, making effective treatment of brain tumors and neurodegenerative diseases such as multiple sclerosis, Parkinson's, Huntington’s and Alzheimer's diseases nearly impossible. Thus, ways to transiently disrupt the BBB in a controlled and localized manner are of need for efficient treatment of brain diseases. Our in vitro and in vivo results clearly demonstrate that this can be obtained non-invasively by applying low pulsed electric fields (L-PEFs).

Background

Currently, there is no state-of-the-art approach for inducing BBB disruption (BBBd) despite extensive efforts. Focused ultrasound (FUS) is the only non-invasive localized approach. Although showing promise, concerns regarding long term safety were raised. On top of this, the treatment requires the use of a stereotactic frame under MRI guidance and takes several ours. Other approaches include microspheres, colloidal carrier systems, and new formulations of existing drugs that can cross the BBB, all at various stages of pre-clinical and clinical studies, but it has been suggested that the effect is limited by relatively low doses that reach the brain. Our mission is to develop a device for inducing transient BBBd using L-PEFs that will enable efficient delivery of systemically administered therapeutic agents for treatments of brain tumors, neurodegenerative diseases and other CNS pathologies, and extraction of unwanted substances from the brain to the blood system.

The Innovation

We have developed a novel method to induce transient BBBd enabling passage of Biologics such as monoclonal antibodies and RNA therapeutics using L-PEFs. This type of pulses induces BBBd via the paracellular pathway, i.e by transiently affecting the function of tight junction and adherent junction protein.

The treatment may be applied using a non-invasive or invasive system. The treatment may be applied by direct voltage/current inducing electrical fields in the CNS or by inducing electromagnetic fields in the CNS.

Advantages

Scalable

• The treatment can be localized to a specific brain or spine structure/lesion/tumor or can be applied to large tissue volumes or even the entire brain or spine.
• The treatment can enhance the efficacy of existing drugs or can be combined in the development of new CNS Biologics such as monoclonal antibodies and RNA therapeutics. 

Safe, transient, short and repeatable

• The treatment was found to be safe in rodents
• Depending on treatment parameters, BBBd duration is several minutes to 3 hours
• The treatment duration is only seconds-minutes
• The treatment cab be repeated as needed

Home treatment

• As the treatment is short and non-invasive, it can be performed by the patient at home, as a single or repeated treatment

The neurological/neurodegenerative drug market is a competitive market comprising large number of players with wide range of products and ongoing R&D studies. The key players are F. Hoffmann La-Roche, Ltd., Ossianix, Inc., Eli Lilly and Company, Bristol-Myers Squibb, Sanofi Genzyme, biOasia Technologies, Inc., Envivo Pharmaceuticals, Inc., Sagetis Biotech, Janssen Pharmaceutica NV, and ArmaGen.

Development Program

Our in vitro and in vivo results represent a proof of concept for inducing transient BBBd, enabling delivery of small/large molecules into the brain, using L-PEFs. Following treatment protocol optimization, we will focus on a first application (ALS or cortical primary brain tumors) and a prototype system (electrodes/pulse-generator/planning software) will be designed & constructed. Efficacy for specific diseases will be optimized using rodents, in parallel to safety studies in pigs. Finally, we will develop a tool for human personalized treatment planning and submit an IRB proposal for a first-in-human clinical trial. In parallel, prototypes for addition applications will be designed and developed.

• Sharabi et al, Transient BBB disruption is induced by low pulsed electrical fields in vitro: an analysis of permeability and trans-endothelial electric resistivity. Drug Deliv. 2019.
• Sharabi et al, Non-Invasive Low Pulsed Electrical Fields for Inducing BBB Disruption in mice - feasibility  demonstration. Pharmaceutics. 2021.