Last update 01 Nov 2024

LIPA

Last update 01 Nov 2024

Basic Info

Synonyms

Acid cholesteryl ester hydrolase, CESD, Cholesteryl esterase

+ [6]

Introduction

Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.

Drugs associated with LIPA

Sebelipase Alfa

Target

LIPA

Mechanism

LIPA modulators

Active Org.

AstraZeneca Korea Ltd. [+5]

Originator Org.

Alexion Pharmaceuticals, Inc.

Active Indication

Cholesterol Ester Storage Disease [+1]

Inactive Indication

Failure to Thrive [+2]

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

EU [+3]

First Approval Date28 Aug 2015

LIPA cDN AAV gene therapy(Genethon)

Target

LIPA

Mechanism

LIPA modulators

Active Org.

Genethon

Originator Org.

Genethon

Active Indication

Wolman Disease

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ERX-41

Target

LIPA

Mechanism

LIPA inhibitors

Active Org.

The University of Texas System [+2]

Originator Org.

The University of Texas System

Active Indication

Metastatic breast cancer [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with LIPA

EUCTR2014-000533-22-IT / Not yet recruitingPhase 2

A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants with Rapidly Progressive Lysosomal Acid Lipase Deficiency

Start Date18 Sep 2014

Sponsor / Collaborator

Synageva BioPharma Corp.

NCT02112994 / CompletedPhase 2

A Multi-Center, Open-Label Study of Sebelipase Alfa in Patients With Lysosomal Acid Lipase Deficiency

This study evaluated the safety and efficacy of sebelipase alfa in a broad population of participants with lysosomal acid lipase deficiency (LAL-D).

Start Date24 Jun 2014

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

NCT02193867 / TerminatedPhase 2

A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency

This was an open-label, repeat-dose, study of sebelipase alfa in infants with rapidly progressive lysosomal acid lipase deficiency (LAL-D). Eligible participants received once-weekly infusions of sebelipase alfa for up to 3 years.

Start Date06 Jun 2014

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

100 Clinical Results associated with LIPA

100 Translational Medicine associated with LIPA

0 Patents (Medical) associated with LIPA

1,150

Literatures (Medical) associated with LIPA

31 Dec 2024·mAbs

Illuminating a biologics development challenge: systematic characterization of CHO cell-derived hydrolases identified in monoclonal antibody formulations

Article

Author: Studts, Joey ; Lakatos, Daniel ; Maier, Melanie ; Schulz, Patrick ; Felix, Marius Nicolaus ; Weiß, Linus ; Fischer, Simon ; Franzreb, Matthias ; Schmidt, Moritz ; Zeh, Nikolas ; Schmieder-Todtenhaupt, Valerie ; Heinzelmann, Daniel ; Otte, Kerstin ; Lindner, Benjamin ; Dehghani, Alireza ; Reisinger, Bernd

Monoclonal antibodies (mAb) and other biological drugs are affected by enzymatic polysorbate (PS) degradation that reduces product stability and jeopardizes the supply of innovative medicines. PS represents a critical surfactant stabilizing the active pharmaceutical ingredients, which are produced by recombinant Chinese hamster ovary (CHO) cell lines. While the list of potential PS-degrading CHO host cell proteins (HCPs) has grown over the years, tangible data on industrially relevant HCPs are still scarce. By means of a highly sensitive liquid chromatography-tandem mass spectrometry method, we investigated seven different mAb products, resulting in the identification of 12 potentially PS-degrading hydrolases, including the strongly PS-degrading lipoprotein lipase (LPL). Using an LPL knockout CHO host cell line, we were able to stably overexpress and purify the remaining candidate hydrolases through orthogonal affinity chromatography methods, enabling their detailed functional characterization. Applying a PS degradation assay, we found nine mostly secreted, PS-active hydrolases with varying hydrolytic activity. All active hydrolases showed a serine-histidine-aspartate/glutamate catalytical triad. Further, we subjected the active hydrolases to pH-screenings and revealed a diverse range of activity optima, which can facilitate the identification of residual hydrolases during bioprocess development. Ultimately, we compiled our dataset in a risk matrix identifying PAF-AH, LIPA, PPT1, and LPLA2 as highly critical hydrolases based on their cellular expression, detection in purified antibodies, active secretion, and PS degradation activity. With this work, we pave the way toward a comprehensive functional characterization of PS-degrading hydrolases and provide a basis for a future reduction of PS degradation in biopharmaceutical drug products.

01 Aug 2024·Cancer Research Communications

ANGPTL4 Suppresses Clear Cell Renal Cell Carcinoma via Inhibition of Lysosomal Acid Lipase

Article

Author: Tithi, Tanzia Islam ; Zhang, Weizhou ; Kolb, Ryan ; De, Umasankar ; Carelock, Madison E. ; Nataraj, Akhila ; Jin, Zeng ; Jolley, Elena ; Kleberg, Jeremy ; Davies, Brandon S.

AbstractRenal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau(WT VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with WT VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases LAL activity in ccRCC cells. These data suggest that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.Significance:Our data indicate angiopoietin-like 4 (ANGPTL4) acts as a tumor suppressor in clear cell renal cell carcinoma via regulating lipid metabolism and identifies a cohort of patients with lower expression of ANGPTL4 that are correlated with shorter survival.

01 Jul 2024·Journal of Clinical Laboratory Analysis

Frequency of rs1051338 and rs116928232 Variants in Individuals from Northwest Mexico

Article

Author: Giraldo, Pilar ; Hernández‐Orozco, Angélica Alejandra ; Cebolla, Jorge J. ; Melendez‐Aranda, Lennon ; Mendoza‐Ruvalcaba, Sandra del Carmen ; Perea‐Díaz, Francisco Javier ; García‐Ortíz, José Elías ; Brambila‐Tapia, Aniel Jessica Leticia

ABSTRACTBackgroundLIPA, situated on chromosome 10q23.2‐q23.3, encodes the enzyme lysosomal acid lipase (LAL) (EC 3.1.1.13). Genetic alterations in LIPA lead to lysosomal acid lipase deficiency (LALD), an inborn error causing lipid metabolism anomalies and impairing cholesterol and triacylglyceride degradation. Over 40 LIPA variants have been documented, yet this study focuses on just two. The rs1051338 variant (NM_000235:c.46A>C) affects the signal peptide in Exon 2, whereas rs116928232, located in Exon 8, alters the splice site (NM_000235:c.894G>A), impacting lysosomal acid lipase activity. Considering the diverse clinical manifestations of LALD and the rising hepatic steatosis prevalence in Mexican population, mainly due to diet, these variants were investigated within this demographic to uncover potential contributing factors. This study aimed to reveal the frequency of rs1051338 and rs116928232 among healthy mestizo individuals in Northwest Mexico, marking a significant genetic exploration in this demographic.MethodsThree hundred ten healthy mestizo individuals underwent PCR‐RFLP analysis for both variants, and Sanger sequencing was performed for variant rs116928232. Bioinformatic analysis was also performed to predict protein changes.ResultsAllele frequencies for rs1051338 (FA = 0.39, p value = 0.15) and rs116928232 (FA = 0.0016, p value = 0.49) aligned with reported data, while bioinformatic analysis allowed us to identify the protein alteration observed in both variants; finally, the variants showed no linkage between them (normalized D′ = 1.03, p value = 0.56).ConclusionsAllelic frequencies closely matched reported data, and protein structure analysis confirmed variant impacts on LAL enzyme function. Notably, this study marks the first analysis of rs1051338 and rs116928232 in a healthy Mexican mestizo population.

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