CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Abstract

During the past decades, several therapeutic approaches have been developed and made rapidly available for many patients afflicted with lysosomal storage disorders (LSDs), inborn organelle disorders with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes. These conditions are individually rare, but, collectively, their incidence ranges from 1 in 2,315 to 7,700 live-births. Most LSDs are manifested by neurological symptoms or signs, including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. The chronic and later-onset clinical forms are at one end of the continuum spectrum and are characterized by a subtle and slow progression of neurological symptoms. Due to its inherent physiological properties, unfortunately, the blood-brain barrier (BBB) constitutes a significant obstacle for current and upcoming therapies to achieve the central nervous system (CNS) and treat neurological problems so prevalent in these conditions. To circumvent this limitation, several strategies have been developed to make the therapeutic agent achieve the CNS. This narrative will provide an overview of current therapeutic strategies under development to permeate the BBB, and address and unmet need for treatment of the progressive neurological manifestations, which are so prevalent in these inherited lysosomal disorders.

Keywords: enzyme replacement therapy; exosomes; extracellular vesicles; gene therapy; liposomes; lysosomes; small molecules; therapy.

Figure 1

Blood-brain barrier (BBB) in the context of CNS-targetting therapeutics. (A) The central nervous system (CNS), and the cerebrovascular system are protected by a series of robust membranes as dura, arachnoid and pia mater. (B) The components of the BBB are established by the dynamic relationship among astrocytes endfeet, basal membrane, pericytes, endothelial cells and the tight junctions between the brain-endothelial cells. An illustration of the cross-section of a CNS-capillary shows the BBB components (italized), and current therapies under investigation. The modified chimeric lysosomal enzymes (LysoEnz), small molecules, gene therapy exploring specific AAV serotypes, and nanoparticle-based therapies (Exo-LysoEnzy) are designed to overcome the BBB and tackle the neuropathogenesis processes prevalent in many LSDs.

Figure 2

The nanocarrier-based delivery systems proposed for the treatment of lysosomal storage diseases include exosomes (A), liposomes (B), and nanoparticles (C). (A) Exosomes as physiological extracellular vesicles produced by cells and contain specific protein- and lipid-based markers and also carry various metabolites, nucleic acids and proteins as cargo. (B) Liposome surface can be derivatized to contain targeting molecules, such as antibodies, GNeo, and other molecules, which are often attached to the liposomes after prior coating with polyethylene glycol (PEG). (C) Nanoparticles, such as here shown polymeric nanoparticle can be modified by the presence of peptides, aptamers, antibodies, and other molecules to increase their targeting efficiency.