Advances in therapies for neurological lysosomal storage disorders

Abstract

Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.

AAV-mediated gene therapy for Sialidosis

“…It is well established that the brain is an exceedingly difficult tissue to treat via gene therapy due to the presence of the blood-brain-barrier, especially following a systemic injection route 20 . Thus, we wanted to determine whether the expression of the transgene products in different brain regions of treated mice would parallel the biodistribution of the two AAV vectors.…”

“…The AAV serotype 2 was the first to be vectorized and several pseudo-types have been generated with cell- or tissue-specific tropism 25,26 . These vectors achieve stable transgene expression, and have been extensively employed in pre-clinical studies on various disease models as well as in clinical trials 27 28–45 Several AAV-mediated gene therapy clinical trials, which have been approved by both the Food and Drug Administration and the European Medicines Agency, 24 are currently in place for different LSDs, including Gaucher disease, GM1- and GM2-gangliosidoses, Krabbe disease, several mucopolysaccharidoses (I, II, IIIA, B, C, D, VII), metachromatic leukodystrophy, Pompe disease, Batten disease (neuronal ceroid lipofuscinoses; CLN1 – 8), Fabry disease, and Danon disease 20,46–50 .…”

Optical recordings of organellar membrane potentials and the components of membrane conductance in lysosomes

“…Currently, there is great interest in studying the ion fluxes across the lysosomal membrane, which are regulated by a distinct set of channels and transporters (Chen et al., 2017; Li et al., 2019; Sterea et al., 2018; Xu et al., 2015). These have been implicated in various human pathological conditions associated with lysosomal storage diseases, such as neurodegenerative diseases, metabolic disorders and cancer (Ellison et al., 2023; Pfrieger, 2023; Shin et al., 2019; Toledano‐Zaragoza & Ledesma, 2020). Lysosomal storage diseases can arise from mutations in lysosomal enzymes, but naturally occurring variations in the expression and/or function of lysosomal ion channels and transporters can also lead to lysosomal storage diseases (Bissa et al., 2016; Cao et al., 2015; Feng et al., 2018; Huizing & Gahl, 2020; Kendall & Holian, 2021; Onyenwoke et al., 2015; Riederer et al., 2023; Shen et al., 2012; Zhang et al., 2018).…”

Sustained long-term disease correction in a murine model of MPSII following stem cell gene therapy

“…MPSII is a multisystemic disease with a range of characteristic symptoms, including skeletal abnormalities (dysostosis multiplex), joint stiffness and pain, short stature, cardiorespiratory disease, and hepatosplenomegaly. 2 , 3 The most severe form of MPSII, characterized by progressive neurodegeneration and premature death, affects two-thirds of patients, with the majority not surviving into adulthood. 3 , 4 …”

“…2 , 3 The most severe form of MPSII, characterized by progressive neurodegeneration and premature death, affects two-thirds of patients, with the majority not surviving into adulthood. 3 , 4 …”