4.6 Review

Recent insights into lysosomal acid lipase deficiency

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Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis

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Summary: Dysfunction of the macrophage lysosomal system is a characteristic of atherosclerosis, and acidic nanoparticles can be used to rescue this dysfunction and treat the disease.

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Lysosomal acid lipase promotes endothelial proliferation in cold-activated adipose tissue

Alexander W. Fischer et al.

Summary: Endothelial cells play a crucial role in the transport and processing of circulating nutrients and maintenance of tissue homeostasis. Recent studies have shown that capillary endothelial cells in thermogenic adipose tissues take up and metabolize triglyceride-rich lipoprotein particles in response to cold exposure, and this process is dependent on specific proteins and enzymes. Loss of lysosomal acid lipase in endothelial cells leads to impaired endothelial proliferation and diminished thermogenic adaptation. The processing of lipoproteins by lysosomal acid lipase generates reactive oxygen species, which in turn activate proliferative responses mediated by hypoxia-induced factor. This study provides in vivo evidence for the importance of lysosomal acid lipase in endothelial cells of thermogenic adipose tissue.

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Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study

Barbara K. Burton et al.

Summary: This study reports the final results of using sebelipase alfa enzyme replacement therapy in patients with LAL-D for up to 5 years. It shows that this treatment can sustain improvements in liver function and lipid abnormalities without progression of liver disease.

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Long-Term Sebelipase Alfa Treatment in Children and Adults With Lysosomal Acid Lipase Deficiency

Barbara K. Burton et al.

Summary: This study evaluated the efficacy and safety of sebelipase alfa in patients with LAL-D. The results showed that the treatment was well tolerated and resulted in sustained improvements in liver and lipid parameters.

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Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases

Ivan Bradic et al.

Summary: Our findings demonstrate that Lalistat-1 and Lalistat-2 not only inhibit the action of LAL, but also suppress the activity of cytosolic lipid hydrolases responsible for lysosomal function. This has critical implications for understanding the role of LAL in lysosomal function, signaling pathways, and autophagy.

MOLECULAR METABOLISM (2022)

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Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program

Ursa Sustar et al.

Summary: LAL-D is a lysosomal storage disorder that is often underdiagnosed or misdiagnosed due to similar clinical and laboratory findings with other cholesterol or liver dysfunctions. In a comprehensive familial hypercholesterolemia (FH) screening in Slovenia, LAL-D was screened as a secondary condition, and three children were identified with LAL-D through genetic analysis. Early treatment resulted in improved cholesterol and transaminase levels as well as liver steatosis in these children.

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Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency

Patricia Lam et al.

Summary: LAL-D is a rare genetic disease and gene replacement therapy may be a promising treatment option based on recent clinical studies.

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Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid- derived suppressor cells

Ting Zhao et al.

Summary: LAL deficiency in mice leads to an increase in CD11c+ cells with metabolic changes and oxidative stress. Pharmacological interventions targeting specific metabolic pathways can reduce the immune functions of these cells and reverse their tumor-promoting effects.

JCI INSIGHT (2022)

Review Genetics & Heredity

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

Katrina J. J. Besler et al.

Summary: This review discusses the role of Lysosomal acid lipase (LAL) in lysosomes and its association with genetic mutations in diseases such as Wolman Disease and cholesteryl ester storage disease. Furthermore, the review explores the potential role of LAL in cardiovascular risk and fatty liver disease. It also emphasizes the need for further research on enhancing LAL activity as a novel treatment strategy for reducing the development and regression of ischemic cardiovascular disease and fatty liver.

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Current knowledge on the tissue distribution of mRNA nanocarriers for therapeutic protein expression

Matthias Zadory et al.

Summary: Exogenously delivered mRNA-based drugs are a new class of therapeutics with potential for treating various diseases. Advances in non-viral delivery tools have enabled the evaluation of mRNA for protein replacement therapies, gene editing, and vaccines. However, overcoming the challenge of in vivo delivery to targeted organs and cells remains critical. Evaluating the biodistribution of mRNA vehicles is crucial for the development of effective pharmaceutical candidates. This review discusses recent advances in designing nanoparticles loaded with mRNA and explores key factors influencing their biodistribution after administration. Furthermore, the latest developments in preclinical and clinical translation of mRNA therapeutics for protein supplementation therapy are highlighted.

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Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies

Suresh Vijay et al.

Summary: The findings of the two studies on rapidly progressive LAL-D in infants demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival, improved growth and hematologic parameters, and was generally well tolerated.

ORPHANET JOURNAL OF RARE DISEASES (2021)

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Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth

Katharina B. Kuentzel et al.

Summary: The research showed that defective lysosomal CE catabolism affects placental and fetal cholesterol homeostasis, leading to hepatic lysosomal lipid accumulation in Lal-/- fetuses. After birth, LAL deficiency worsens with massive hepatic lysosomal lipid accumulation, continuing to deteriorate into young adulthood.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up

Tanguy Demaret et al.

Summary: Treating Wolman disease patients with sebelipase alfa replacement therapy showed positive outcomes in terms of survival rate, growth parameters, and HRQoL. Early treatment initiation is crucial for efficacy, and further evaluation of long-term follow-up and alternative treatments is needed.

ORPHANET JOURNAL OF RARE DISEASES (2021)

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Low LAL (Lysosomal Acid Lipase) Expression by Smooth Muscle Cells Relative to Macrophages as a Mechanism for Arterial Foam Cell Formation

Joshua A. Dubland et al.

Summary: The study found that the inherently low level of LAL in SMCs compared with macrophages is associated with reduced capacity to catabolize atherogenic lipoproteins, which is a mechanism for SMC foam cell formation in atherosclerosis.

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (2021)

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Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

Vinay Sachdev et al.

Summary: The study shows that feeding a Western-type diet to Lal-deficient mice triggers metabolic reprogramming, leading to changes in gut-liver cholesterol homeostasis. These metabolic adaptations affect bile acid synthesis, lipoprotein uptake, and cholesterol absorption, ultimately resulting in resistance to diet-induced obesity in LAL-KO mice.
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Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

Jane E. Potter et al.

Summary: The study describes a multimodal treatment approach for Wolman disease patients combining ERT, DSR, and HCT. After receiving HCT, patients showed improved disease phenotype and laboratory parameters, particularly in gastrointestinal symptoms. 4 out of 5 patients are alive, demonstrating the significant benefits of HCT in improving the condition of Wolman disease patients.

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Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet

Michael W. Lopresti et al.

Summary: The hepatic overexpression of LAL does not alleviate the progression of NAFLD, but instead exacerbates inflammation and immune cell infiltration in mice fed a Western diet.

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Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

Camille Gamblin et al.

Summary: LAL plays a crucial role in adipocyte metabolism and cholesterol homeostasis, with overexpression contributing to weight loss and improved glucose tolerance, particularly through the activation of brown adipose tissue thermogenesis.

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