Targeting cerebral diseases with enhanced delivery of therapeutic proteins across the blood-brain barrier

ABSTRACT

Introduction

Cerebral diseases have been threatening public physical and psychological health in the recent years. With the existence of the blood-brain barrier (BBB), it is particularly hard for therapeutic proteins like peptides, enzymes, antibodies, etc. to enter the central nervous system (CNS) and function in diagnosis and treatment in cerebral diseases. Fortunately, the past decade has witnessed some emerging strategies of delivering macromolecular therapeutic proteins across the BBB.

Areas covered

Based on the structure, functions, and substances transport mechanisms, various enhanced delivery strategies of therapeutic proteins were reviewed, categorized by molecule-mediated delivery strategies, carrier-mediated delivery strategies, and other delivery strategies.

Expert opinion

As for molecule-mediated delivery strategies, development of genetic engineering technology, optimization of protein expression and purification techniques, and mature of quality control systems all help to realize large-scale production of recombinant antibodies, making it possible to apply to the clinical practice. In terms of carrier-mediated delivery strategies and others, although nano-carriers/adeno-associated virus (AAV) are also promising candidates for delivering therapeutic proteins or genes across the BBB, some issues still remain to be further investigated, including safety concerns related to applied materials, large-scale production costs, quality control standards, combination therapies with auxiliary delivery strategies like focused ultrasound, etc.

KEYWORDS:

• AAV
• BBB
• Exosomes
• Focused ultrasound
• Liposomes
• Nanoparticles
• Recombinant antibodies
• Therapeutic protein delivery

Article highlights

• Recombinant antibodies and small molecule/peptide-antibody conjugates can cross the BBB by mediation of the BBB-targeting domains.

• Therapeutic proteins can be loaded into/modified onto nano-carriers to cross the BBB and target cerebral diseases.

• Gene delivery by stem cells, macrophages, exosomes, AAV, and other non-viral vectors turns up as an indirect but potential strategy by generating therapeutic protein in vivo, particularly in the brain.

• Focused ultrasound, opening the BBB transiently, provides an auxiliary strategy for therapeutic protein delivery to the brain.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was supported by Shanghai Education Commission Major Project (No. 2017-01-07-00-07-E00052), National Natural Science Foundation of China (No. 81690263)