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.

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal

“… 34 , 38 It should be borne in mind that MPSIIIA is caused by mutations in a secretable lysosomal enzyme that can correct the enzymatic deficit of non-transduced cells through cross-correction. Preclinical and clinical data with intra-CSF ERT for several different secretable lysosomal enzymes 52 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 suggest that therapeutic efficacy can be expected not only from direct vector transduction but also from the presence of the enzyme in the CSF. Differences in transgene expression were somewhat more pronounced in the spinal cord and DRGs.…”

The Role of Exosomes in Lysosomal Storage Disorders

“…Since these vesicles can carry cargo between adjacent cells and organs, and efficiently cross the blood–brain barrier [ 59 ], they are attractive candidates for drug development. [ 60 ].…”

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias

“…Although many of the ERTs listed here gained FDA approval by demonstrating positive effect on physical function (e.g. 6‐min walk test), decreased pain and improved radiographic skeletal scores (Akyol et al, 2019; Hughes et al, 2017), key neurologic LSD manifestations are not improved due to the inability of ERT to cross the blood brain barrier (Edelmann & Maegawa, 2020). New therapeutic avenues to overcome this obstacle are under investigation and reviewed elsewhere including intrathecal enzyme replacement, gene therapy, substrate reduction therapy and use of pharmaceutical chaperones.…”