RARE DISEASE
Apolipoprotein A-I deficiency
Apolipoprotein A-I deficiency
Apolipoprotein A-I deficiency
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Drug discovery
1
drug
With orphan designation
Overview
Apolipoprotein A-I deficiency is a rare autosomal recessive disorder characterized by extremely low HDL cholesterol (<10 mg/dL) and ApoA-I levels (<20 mg/dL) due to pathogenic APOA1 gene variants. Impaired cholesterol efflux increases coronary artery disease (CAD) risk, often manifesting as premature CAD (before age 50), corneal opacities, and xanthomas. Associated systemic amyloidosis or neurological symptoms occur in some mutations. Diagnosis requires genetic confirmation and differentiation from other HDL deficiencies (e.g., Tangier disease) [1][6][11].
Burden
Premature CAD (e.g., myocardial infarction in mid-30s) and recurrent events requiring intervention [2][6][16].
Heterogeneity: Some mutations cause amyloidosis (hepatic, renal, or cardiac failure); others present asymptomatically [6][11].
Lifetime management costs due to chronic CVD monitoring and advanced therapies (e.g., gene therapy) [1][3][18].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
329 drug discovery papers about Apolipoprotein A-I deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
329 drug discovery papers about Apolipoprotein A-I deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-11-27 | From HDL Deficiency to Neuropathy: Insights into Tangier Disease
Introduction: This review aims to provide a comprehensive examination of Tangier disease, focusing on its clinical manifestations, pathophysiology, and diagnostic methods. The article also delves into the available management strategies, the challenges in treating this rare condition, and the ongoing research into potential therapeutic interventions. Materials and Methods: A comprehensive review of the literature was conducted using the PubMed and Google Scholar databases with the following keywords: "Tangier disease", "HDL deficiency", "ABCA1", "neuropathy", "high-density lipoprotein ", "HDL", "apoA-I", "CETP", "atherosclerosis", "splenomegaly". Summary: Tangier disease is a rare autosomal recessive genetic disorder caused by mutations in the ABCA1 gene, which impairs cholesterol transport and results in low levels of HDL. This leads to the accumulation of cholesterol esters in various tissues, including the tonsils, spleen, lymph nodes, and nerves. The disease is characterized by orange-colored, enlarged tonsils, splenomegaly, peripheral neuropathy, and a heightened risk for atherosclerotic cardiovascular disease. Diagnosis is confirmed through low HDL and apoA-I levels, along with genetic testing for ABCA1 mutations. While no cure exists, treatment focuses on symptom management, controlling cardiovascular risks, and improving HDL function through lifestyle and dietary changes. Conclusions: Tangier disease, a rare genetic disorder caused by mutations in the ABCA1 gene, leads to severe lipid imbalances and various systemic complications. Although there is no cure, managing symptoms, controlling cardiovascular risks, and adopting lifestyle changes are essential for improving outcomes. Ongoing research into gene therapies and new treatments offers hope for future breakthroughs.
2025-11-22 | Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.
In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both LDL and HDL cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unravelled. Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with a MEK1 inhibitor to block ERK signalling. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to examine HDL size and composition in human cohort studies. Investigation in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (without changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational up-regulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolaemia may not only lower plasma levels of LDL cholesterol but also HDL cholesterol.
2025-09-01 | Effect of Extra Virgin Olive Oil High in Bioactive Compounds on Atherosclerosis in Apoe-Deficient Mice.
To test the effects of extra virgin olive oil (EVOO) enriched in specific bioactive compounds (EVOO HBC) on atherosclerosis and fatty liver, three isocaloric Western diets differing in the type of fat (palm, EVOO, or EVOO HBC) were fed to Apoe-deficient mice for 12 weeks. Plasma lipids, lipoprotein characterization, circulating CD36-expressing monocytes, and M2 peritoneal macrophages were quantified. Hepatic squalene and cross-sectional and en face atherosclerotic lesions were analyzed. Compared to the palm group, plasma triglyceride and glucose levels increased, while APOA1, paraoxonase 1 activity, and lipoprotein oxidation decreased in mice fed both EVOO groups. The latter stored liver squalene according to the amount consumed. En face and cross-sectional atherosclerotic lesions were lower in the EVOO groups. CD36 expression in circulating monocytes was lower and M2 peritoneal macrophages were higher in the EVOO groups. In males, there was a reduced presence of CD68-expressing cells in atherosclerotic plaques, while in females, there was a reduction in en face lesions that negatively correlated with high-density lipoprotein (HDL)-phospholipid efflux. The recruitment of macrophages into atherosclerotic plaques and the improvement of HDL efflux may be sex-dependent and attributable to the high content of squalene and a specific oleuropein aglycone.
2025-08-30 | Apolipoprotein A (ApoA) in Neurological Disorders: Connections and Insights.
Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood-brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer's disease (AD), stroke, Parkinson's disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy.
2025-03-15 | The lack of apoA-I in apoE-KO mice affects the liver transcriptome.
Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development. Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism. The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.
2025-11-27 | From HDL Deficiency to Neuropathy: Insights into Tangier Disease
Introduction: This review aims to provide a comprehensive examination of Tangier disease, focusing on its clinical manifestations, pathophysiology, and diagnostic methods. The article also delves into the available management strategies, the challenges in treating this rare condition, and the ongoing research into potential therapeutic interventions. Materials and Methods: A comprehensive review of the literature was conducted using the PubMed and Google Scholar databases with the following keywords: "Tangier disease", "HDL deficiency", "ABCA1", "neuropathy", "high-density lipoprotein ", "HDL", "apoA-I", "CETP", "atherosclerosis", "splenomegaly". Summary: Tangier disease is a rare autosomal recessive genetic disorder caused by mutations in the ABCA1 gene, which impairs cholesterol transport and results in low levels of HDL. This leads to the accumulation of cholesterol esters in various tissues, including the tonsils, spleen, lymph nodes, and nerves. The disease is characterized by orange-colored, enlarged tonsils, splenomegaly, peripheral neuropathy, and a heightened risk for atherosclerotic cardiovascular disease. Diagnosis is confirmed through low HDL and apoA-I levels, along with genetic testing for ABCA1 mutations. While no cure exists, treatment focuses on symptom management, controlling cardiovascular risks, and improving HDL function through lifestyle and dietary changes. Conclusions: Tangier disease, a rare genetic disorder caused by mutations in the ABCA1 gene, leads to severe lipid imbalances and various systemic complications. Although there is no cure, managing symptoms, controlling cardiovascular risks, and adopting lifestyle changes are essential for improving outcomes. Ongoing research into gene therapies and new treatments offers hope for future breakthroughs.
2025-11-22 | Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.
In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both LDL and HDL cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unravelled. Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with a MEK1 inhibitor to block ERK signalling. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to examine HDL size and composition in human cohort studies. Investigation in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (without changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational up-regulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolaemia may not only lower plasma levels of LDL cholesterol but also HDL cholesterol.
2025-09-01 | Effect of Extra Virgin Olive Oil High in Bioactive Compounds on Atherosclerosis in Apoe-Deficient Mice.
To test the effects of extra virgin olive oil (EVOO) enriched in specific bioactive compounds (EVOO HBC) on atherosclerosis and fatty liver, three isocaloric Western diets differing in the type of fat (palm, EVOO, or EVOO HBC) were fed to Apoe-deficient mice for 12 weeks. Plasma lipids, lipoprotein characterization, circulating CD36-expressing monocytes, and M2 peritoneal macrophages were quantified. Hepatic squalene and cross-sectional and en face atherosclerotic lesions were analyzed. Compared to the palm group, plasma triglyceride and glucose levels increased, while APOA1, paraoxonase 1 activity, and lipoprotein oxidation decreased in mice fed both EVOO groups. The latter stored liver squalene according to the amount consumed. En face and cross-sectional atherosclerotic lesions were lower in the EVOO groups. CD36 expression in circulating monocytes was lower and M2 peritoneal macrophages were higher in the EVOO groups. In males, there was a reduced presence of CD68-expressing cells in atherosclerotic plaques, while in females, there was a reduction in en face lesions that negatively correlated with high-density lipoprotein (HDL)-phospholipid efflux. The recruitment of macrophages into atherosclerotic plaques and the improvement of HDL efflux may be sex-dependent and attributable to the high content of squalene and a specific oleuropein aglycone.
2025-08-30 | Apolipoprotein A (ApoA) in Neurological Disorders: Connections and Insights.
Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood-brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer's disease (AD), stroke, Parkinson's disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy.
2025-03-15 | The lack of apoA-I in apoE-KO mice affects the liver transcriptome.
Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development. Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism. The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Apolipoprotein A-I deficiency.
1 orphan drug designation for Apolipoprotein A-I deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human apolipoprotein A-I in a complex with phospholipids | proteins | EMA | 2014-08-22 | — | Cerenis Therapeutics Holding SA |
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