RARE DISEASE
Abetalipoproteinemia
Abetalipoproteinemia
Abetalipoproteinemia
Synonyms: Bassen-Kornzweig disease, Homozygous familial hypobetalipoproteinemia
Synonyms: Bassen-Kornzweig disease, Homozygous familial hypobetalipoproteinemia
Synonyms: Bassen-Kornzweig disease, Homozygous familial hypobetalipoproteinemia
Drug discovery
129
papers
On emerging therapies
Overview
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by mutations in the MTTP gene, impairing assembly of apolipoprotein B-containing lipoproteins. This results in fat malabsorption and severe deficiencies of fat-soluble vitamins (A, D, E, K). Clinical features include failure to thrive, steatorrhea, acanthocytosis, and progressive neuromuscular, ophthalmological (e.g., retinitis pigmentosa), and hematological complications. Early diagnosis via lipid panels (LDL-C <15 mg/dL, apoB <15 mg/dL) and genetic testing is critical. Management focuses on low-fat diets, medium-chain triglyceride (MCT) supplementation, and high-dose fat-soluble vitamins to mitigate complications [1][2][3][6].
Burden
Untreated ABL causes irreversible blindness, ataxia, and respiratory failure, often fatal by the third decade [4][9]. Early treatment extends survival into the eighth decade but cannot fully restore function, necessitating lifelong multidisciplinary care [3][6][9]. Registry studies highlight unmet needs for novel therapies [4][9].
Therapies
Diet: Restriction of long-chain fats (<30% total calories) with MCT substitution to reduce steatorrhea [3][13].
Vitamins: High-dose vitamin E (100–400 IU/kg/day) to prevent neurodegeneration; vitamins A, D, K supplementation to address deficiencies [3][4][16].
Monitoring: Regular lipid panels, vitamin levels, and neurologic/ophthalmologic evaluations to guide therapy and avoid toxicity [3][4].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
129 drug discovery papers about Abetalipoproteinemia. Recent publications:
129 drug discovery papers about Abetalipoproteinemia. Recent publications:
categories:
Small molecules
small molecules
2026-08-01 | EP1842 - LBA_ECE_1005 - Homozygous familial hypobetalipoproteinemia with abetalipoproteinemia-like phenotype: a rare multisystemic substrate crisis with negative MTTP sequencing
Abstract Introduction Abetalipoproteinemia (ABL) and Homozygous Familial Hypobetalipoproteinemia (HHBL) are ultra-rare lipid metabolism disorders. While ABL is typically caused by MTTP mutations, HHBL results from codominant APOB mutations. Both lead to a near-complete absence of apolipoprotein B-containing lipoproteins, creating a critical substrate crisis for fat-soluble vitamins and cholesterol, which precipitates hepatic, hematologic, and neuro-ophthalmological dysfunction. Case Presentation A 28-year-old female presented with menstrual irregularities, fatigue, and persistent steatorrhea. Laboratory screening revealed severe hypolipidemia (LDL-C <5 mg/dL). Diagnosis was confirmed by ApoB <20 mg/dL, Vitamin E 2.36 µg/mL (critical deficiency), and Vitamin A 520 ng/mL. Hormonal evaluation showed suppressed Estradiol (26 pg/mL). Peripheral smear demonstrated pathognomonic acanthocytosis. Multidisciplinary screening revealed no irreversible pathologies. Hepatobiliary USG showed hepatomegaly (15.5 cm) with Grade 2 steatosis. Family screening confirmed a familial pattern: the 52-year-old father and 50-year-old mother exhibited significant asymptomatic hypolipoproteinemia (LDL-C: 27.8 and 61 mg/dL, respectively). Although there is no known consanguinity, both parents originate from the same small geographical region (approximately ≤250 000 inhabitants), suggesting a potential founder effect. This profile directs the diagnosis toward HHBL despite the severe phenotype. Genetic Evaluation: Targeted MTTP sequencing detected no pathogenic mutations. Since MTTP defects are a regulatory prerequisite for official orphan drug access (eg, Lomitapide), the patient was ineligible for such targeted therapies. To explore the underlying pathology explaining this favorable clinical course, an expanded genetic panel is currently pending. Management & Conclusion Management involved a strict Low-LCT diet supplemented with Medium-Chain Triglyceride (MCT) oil. Initially, high-dose oral Vitamin E (400 IU 2 × 3) and Vitamin A (30 000 IU 1 × 3) were administered. The high cost of orphan drugs and the non-orphan status of MCT oil posed significant therapeutic barriers. Due to clinical stabilization and financial constraints, treatment was optimized to daily maintenance doses (1 × 1), aligning with state-covered insurance limits. This case underscores the challenges in drug access when canonical markers are absent. Aggressive ADEK supplementation remains the gold standard for stabilizing this phenotype, even when advanced pharmacological options are inaccessible.
2026-04-28 | Curcumin-Piperine Combination for Chaperone-Mediated MTP Folding
Curcumin acts as a pharmacological chaperone that can stabilize misfolded proteins, while piperine enhances curcumin bioavailability by inhibiting hepatic glucuronidation. This combination could assist in proper folding of mutant MTP proteins in abetalipoproteinemia patients with missense mutations, similar to its demonstrated effects on other misfolded proteins like transthyretin.
2026-04-28 | Berberine for Intestinal MTP Expression via AMPK-FXR Signaling
Berberine activates AMPK while also functioning as a farnesoid X receptor (FXR) modulator, leading to enhanced expression of genes involved in lipid absorption including intestinal MTP. This dual mechanism could partially restore chylomicron formation capacity while improving overall metabolic function in abetalipoproteinemia patients.
2026-04-28 | Schisandrin B from TCM for MTP Expression Enhancement via Nrf2 Activation
Schisandrin B, a dibenzo[a,c]cyclooctadiene lignan from Schisandra chinensis, activates the Nrf2-ARE pathway leading to enhanced transcription of antioxidant genes. This mechanism could potentially upregulate microsomal triglyceride transfer protein (MTP) expression through Nrf2-mediated protection of hepatocytes from oxidative stress, which is known to suppress MTP function in abetalipoproteinemia.
2026-04-28 | Ashwagandha Withanolides for Hepatic MTP Gene Expression via PPAR-α Activation
Withanolide A and withanoside IV from Withania somnifera act as selective PPAR-α agonists, enhancing hepatic lipid metabolism gene expression including MTP. These compounds also reduce ER stress through activation of the unfolded protein response, potentially addressing both the metabolic dysfunction and cellular stress components of abetalipoproteinemia.
gene therapies
2026-09-13 | Abetalipoproteinemia With a Novel Microsomal Triglyceride Transfer Protein Gene Mutation and Unique Oxidized Lipoprotein Levels.
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene, resulting in the defective secretion of apolipoprotein B (APOB)-containing lipoproteins. Although ABL can theoretically have a low risk of cardiovascular disease (CVD) due to the defective secretion of APOB-containing lipoproteins, the previously reported cases of ABL are limited and its CVD-related pathophysiology thus remains unestablished. We encountered a 25-year-old male patient with very low levels of lipids and lipoproteins. In addition to observing his signs and symptoms, we assayed serum oxidized forms of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles using an enzyme-linked immunosorbent assay (ELISA). Variants in the APOB and MTTP genes were analyzed using next-generation sequencing (NGS). As a result, the patient exhibited low levels of total cholesterol (TC), triglycerides (TGs), LDL-cholesterol, and HDL-cholesterol. The oxidized LDL level was measured under a detectable limit, while oxidized HDL showed a relatively high level. An in-frame deletion in MTTP (p.Ser615del), a novel type of gene mutation, was identified in a homozygous manner. The patient had no obvious signs or symptoms of fat malabsorption or any neurological manifestations. In summary, we described a case of ABL with a novel MTTP mutation, p.Ser615del, without typical signs or symptoms. There were markedly low levels of atherogenic lipids and oxidized LDL, while the relatively high level of oxidized HDL with the low level of HDL-cholesterol appeared, which might offer unique insights into the pathophysiology of CVD-related risk in ABL. Further data accumulation of ABL is expected to clarify the disease picture.
2022-08-01 | Leu351Arg in apoB, a new missense variant causing familial hypobetalipoproteinemia
Background and Aims : Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Here, we identified a rare missense variant in APOB, p.Leu351Arg, in a family presenting with a FHBL phenotype. Despite its co-segregation with FHBL in the proband and her two children, this variant was classified as variant of uncertain significance (VUS) according to the The American College of Medical Genetics and Genomics (ACMG) guidelines. To test if the FHBL phenotype resulted from p.Leu351Arg, we edited hepatic cells and tested the impact of this variant on the full length apoB-100 hepatic synthesis and secretion.Methods: We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in HuH7 cells using CRISPR-Cas9 technology. ApoB synthesis and secretion were explored by digital droplet PCR and ELISA quantification.Results: APOB expression was decreased by 70% in heterozygous APOB-KO cells and almost abolished in homozygous-KO cells, with a consistent decrease in apoB production and secretion. APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant.Conclusions: As the p.Leu351Arg impairs apoB secretion, we classified this new variant as likely pathogenic, proposed a hepatic follow-up and a cascade screening of relatives in this family. To date, this is the first assessment the pathogenicity of VUS in FHBL, using genome editing of human liver cells. This proof-of-principle experiment will allow a global exploration of others VUS found in dyslipidemic patients and to propose a personalized follow-up of these patients. Background and Aims : Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Here, we identified a rare missense variant in APOB, p.Leu351Arg, in a family presenting with a FHBL phenotype. Despite its co-segregation with FHBL in the proband and her two children, this variant was classified as variant of uncertain significance (VUS) according to the The American College of Medical Genetics and Genomics (ACMG) guidelines. To test if the FHBL phenotype resulted from p.Leu351Arg, we edited hepatic cells and tested the impact of this variant on the full length apoB-100 hepatic synthesis and secretion. Methods: We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in HuH7 cells using CRISPR-Cas9 technology. ApoB synthesis and secretion were explored by digital droplet PCR and ELISA quantification. Results: APOB expression was decreased by 70% in heterozygous APOB-KO cells and almost abolished in homozygous-KO cells, with a consistent decrease in apoB production and secretion. APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Conclusions: As the p.Leu351Arg impairs apoB secretion, we classified this new variant as likely pathogenic, proposed a hepatic follow-up and a cascade screening of relatives in this family. To date, this is the first assessment the pathogenicity of VUS in FHBL, using genome editing of human liver cells. This proof-of-principle experiment will allow a global exploration of others VUS found in dyslipidemic patients and to propose a personalized follow-up of these patients.
2017-05-01 | Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTPR46G), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTPR46G iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTPR46G mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.
2011-02-08 | Apolipoprotein B Knockdown by AAV-delivered shRNA Lowers Plasma Cholesterol in Mice
Serum low-density lipoprotein cholesterol (LDL-C) levels are proportionate to the risk of atherosclerotic cardiovascular disease. In order to reduce serum total cholesterol and LDL-C levels in mice, RNA interference (RNAi) was used to inhibit expression of the structural protein of LDL-C, apolipoprotein B100 (ApoB). We developed and screened 19 short hairpin RNAs (shRNAs) targeting conserved sequences in human, mouse, and macaque ApoB mRNAs (shApoB) and subsequently narrowed our focus to one candidate for in vivo testing. Self-complementary adeno-associated virus serotype 8 (scAAV8) was used for long-term transduction of murine liver with shApoB. A strong dose-dependent knockdown of ApoB mRNA and protein was observed, which correlated with a reduction in total cholesterol levels, without obvious signs of toxicity. Furthermore, shApoB was found to specifically reduce LDL-C in diet-induced dyslipidemic mice, whereas high-density lipoprotein cholesterol (HDL-C) remained unaffected. Finally, elevated lipid accumulation was shown in murine liver transduced with shApoB, a known phenotypic side effect of lowering ApoB levels. These results demonstrate a robust dose-dependent knockdown of ApoB by AAV-delivered shRNA in murine liver, thus providing an excellent candidate for development of RNAi-based gene therapy for the treatment of hypercholesterolemia.
2004-01-30 | Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy.
Inherited retinal and choroidal degenerations account for a significant portion of blindness in children and young adults. This article reviews the current status and future prospects for the treatment of these disorders. Current treatment strategies include nutritional intervention for gyrate atrophy of the choroid and retina with hyperornithinemia, abetalipoproteinemia, and Refsum's disease, as well as vitamin A supplementation for retinitis pigmentosa. Future therapeutic prospects include gene therapy for both recessive and dominant disease, secondary gene-based therapies, such as pharmaceutic gene product replacement and treatment with survival factors, anti-apoptotic agents, and calcium blockers, and, finally, stem cell therapy.
small molecules
2026-08-01 | EP1842 - LBA_ECE_1005 - Homozygous familial hypobetalipoproteinemia with abetalipoproteinemia-like phenotype: a rare multisystemic substrate crisis with negative MTTP sequencing
Abstract Introduction Abetalipoproteinemia (ABL) and Homozygous Familial Hypobetalipoproteinemia (HHBL) are ultra-rare lipid metabolism disorders. While ABL is typically caused by MTTP mutations, HHBL results from codominant APOB mutations. Both lead to a near-complete absence of apolipoprotein B-containing lipoproteins, creating a critical substrate crisis for fat-soluble vitamins and cholesterol, which precipitates hepatic, hematologic, and neuro-ophthalmological dysfunction. Case Presentation A 28-year-old female presented with menstrual irregularities, fatigue, and persistent steatorrhea. Laboratory screening revealed severe hypolipidemia (LDL-C <5 mg/dL). Diagnosis was confirmed by ApoB <20 mg/dL, Vitamin E 2.36 µg/mL (critical deficiency), and Vitamin A 520 ng/mL. Hormonal evaluation showed suppressed Estradiol (26 pg/mL). Peripheral smear demonstrated pathognomonic acanthocytosis. Multidisciplinary screening revealed no irreversible pathologies. Hepatobiliary USG showed hepatomegaly (15.5 cm) with Grade 2 steatosis. Family screening confirmed a familial pattern: the 52-year-old father and 50-year-old mother exhibited significant asymptomatic hypolipoproteinemia (LDL-C: 27.8 and 61 mg/dL, respectively). Although there is no known consanguinity, both parents originate from the same small geographical region (approximately ≤250 000 inhabitants), suggesting a potential founder effect. This profile directs the diagnosis toward HHBL despite the severe phenotype. Genetic Evaluation: Targeted MTTP sequencing detected no pathogenic mutations. Since MTTP defects are a regulatory prerequisite for official orphan drug access (eg, Lomitapide), the patient was ineligible for such targeted therapies. To explore the underlying pathology explaining this favorable clinical course, an expanded genetic panel is currently pending. Management & Conclusion Management involved a strict Low-LCT diet supplemented with Medium-Chain Triglyceride (MCT) oil. Initially, high-dose oral Vitamin E (400 IU 2 × 3) and Vitamin A (30 000 IU 1 × 3) were administered. The high cost of orphan drugs and the non-orphan status of MCT oil posed significant therapeutic barriers. Due to clinical stabilization and financial constraints, treatment was optimized to daily maintenance doses (1 × 1), aligning with state-covered insurance limits. This case underscores the challenges in drug access when canonical markers are absent. Aggressive ADEK supplementation remains the gold standard for stabilizing this phenotype, even when advanced pharmacological options are inaccessible.
2026-04-28 | Curcumin-Piperine Combination for Chaperone-Mediated MTP Folding
Curcumin acts as a pharmacological chaperone that can stabilize misfolded proteins, while piperine enhances curcumin bioavailability by inhibiting hepatic glucuronidation. This combination could assist in proper folding of mutant MTP proteins in abetalipoproteinemia patients with missense mutations, similar to its demonstrated effects on other misfolded proteins like transthyretin.
2026-04-28 | Berberine for Intestinal MTP Expression via AMPK-FXR Signaling
Berberine activates AMPK while also functioning as a farnesoid X receptor (FXR) modulator, leading to enhanced expression of genes involved in lipid absorption including intestinal MTP. This dual mechanism could partially restore chylomicron formation capacity while improving overall metabolic function in abetalipoproteinemia patients.
2026-04-28 | Schisandrin B from TCM for MTP Expression Enhancement via Nrf2 Activation
Schisandrin B, a dibenzo[a,c]cyclooctadiene lignan from Schisandra chinensis, activates the Nrf2-ARE pathway leading to enhanced transcription of antioxidant genes. This mechanism could potentially upregulate microsomal triglyceride transfer protein (MTP) expression through Nrf2-mediated protection of hepatocytes from oxidative stress, which is known to suppress MTP function in abetalipoproteinemia.
2026-04-28 | Ashwagandha Withanolides for Hepatic MTP Gene Expression via PPAR-α Activation
Withanolide A and withanoside IV from Withania somnifera act as selective PPAR-α agonists, enhancing hepatic lipid metabolism gene expression including MTP. These compounds also reduce ER stress through activation of the unfolded protein response, potentially addressing both the metabolic dysfunction and cellular stress components of abetalipoproteinemia.
gene therapies
2026-09-13 | Abetalipoproteinemia With a Novel Microsomal Triglyceride Transfer Protein Gene Mutation and Unique Oxidized Lipoprotein Levels.
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene, resulting in the defective secretion of apolipoprotein B (APOB)-containing lipoproteins. Although ABL can theoretically have a low risk of cardiovascular disease (CVD) due to the defective secretion of APOB-containing lipoproteins, the previously reported cases of ABL are limited and its CVD-related pathophysiology thus remains unestablished. We encountered a 25-year-old male patient with very low levels of lipids and lipoproteins. In addition to observing his signs and symptoms, we assayed serum oxidized forms of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles using an enzyme-linked immunosorbent assay (ELISA). Variants in the APOB and MTTP genes were analyzed using next-generation sequencing (NGS). As a result, the patient exhibited low levels of total cholesterol (TC), triglycerides (TGs), LDL-cholesterol, and HDL-cholesterol. The oxidized LDL level was measured under a detectable limit, while oxidized HDL showed a relatively high level. An in-frame deletion in MTTP (p.Ser615del), a novel type of gene mutation, was identified in a homozygous manner. The patient had no obvious signs or symptoms of fat malabsorption or any neurological manifestations. In summary, we described a case of ABL with a novel MTTP mutation, p.Ser615del, without typical signs or symptoms. There were markedly low levels of atherogenic lipids and oxidized LDL, while the relatively high level of oxidized HDL with the low level of HDL-cholesterol appeared, which might offer unique insights into the pathophysiology of CVD-related risk in ABL. Further data accumulation of ABL is expected to clarify the disease picture.
2022-08-01 | Leu351Arg in apoB, a new missense variant causing familial hypobetalipoproteinemia
Background and Aims : Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Here, we identified a rare missense variant in APOB, p.Leu351Arg, in a family presenting with a FHBL phenotype. Despite its co-segregation with FHBL in the proband and her two children, this variant was classified as variant of uncertain significance (VUS) according to the The American College of Medical Genetics and Genomics (ACMG) guidelines. To test if the FHBL phenotype resulted from p.Leu351Arg, we edited hepatic cells and tested the impact of this variant on the full length apoB-100 hepatic synthesis and secretion.Methods: We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in HuH7 cells using CRISPR-Cas9 technology. ApoB synthesis and secretion were explored by digital droplet PCR and ELISA quantification.Results: APOB expression was decreased by 70% in heterozygous APOB-KO cells and almost abolished in homozygous-KO cells, with a consistent decrease in apoB production and secretion. APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant.Conclusions: As the p.Leu351Arg impairs apoB secretion, we classified this new variant as likely pathogenic, proposed a hepatic follow-up and a cascade screening of relatives in this family. To date, this is the first assessment the pathogenicity of VUS in FHBL, using genome editing of human liver cells. This proof-of-principle experiment will allow a global exploration of others VUS found in dyslipidemic patients and to propose a personalized follow-up of these patients. Background and Aims : Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Here, we identified a rare missense variant in APOB, p.Leu351Arg, in a family presenting with a FHBL phenotype. Despite its co-segregation with FHBL in the proband and her two children, this variant was classified as variant of uncertain significance (VUS) according to the The American College of Medical Genetics and Genomics (ACMG) guidelines. To test if the FHBL phenotype resulted from p.Leu351Arg, we edited hepatic cells and tested the impact of this variant on the full length apoB-100 hepatic synthesis and secretion. Methods: We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in HuH7 cells using CRISPR-Cas9 technology. ApoB synthesis and secretion were explored by digital droplet PCR and ELISA quantification. Results: APOB expression was decreased by 70% in heterozygous APOB-KO cells and almost abolished in homozygous-KO cells, with a consistent decrease in apoB production and secretion. APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Conclusions: As the p.Leu351Arg impairs apoB secretion, we classified this new variant as likely pathogenic, proposed a hepatic follow-up and a cascade screening of relatives in this family. To date, this is the first assessment the pathogenicity of VUS in FHBL, using genome editing of human liver cells. This proof-of-principle experiment will allow a global exploration of others VUS found in dyslipidemic patients and to propose a personalized follow-up of these patients.
2017-05-01 | Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTPR46G), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTPR46G iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTPR46G mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.
2011-02-08 | Apolipoprotein B Knockdown by AAV-delivered shRNA Lowers Plasma Cholesterol in Mice
Serum low-density lipoprotein cholesterol (LDL-C) levels are proportionate to the risk of atherosclerotic cardiovascular disease. In order to reduce serum total cholesterol and LDL-C levels in mice, RNA interference (RNAi) was used to inhibit expression of the structural protein of LDL-C, apolipoprotein B100 (ApoB). We developed and screened 19 short hairpin RNAs (shRNAs) targeting conserved sequences in human, mouse, and macaque ApoB mRNAs (shApoB) and subsequently narrowed our focus to one candidate for in vivo testing. Self-complementary adeno-associated virus serotype 8 (scAAV8) was used for long-term transduction of murine liver with shApoB. A strong dose-dependent knockdown of ApoB mRNA and protein was observed, which correlated with a reduction in total cholesterol levels, without obvious signs of toxicity. Furthermore, shApoB was found to specifically reduce LDL-C in diet-induced dyslipidemic mice, whereas high-density lipoprotein cholesterol (HDL-C) remained unaffected. Finally, elevated lipid accumulation was shown in murine liver transduced with shApoB, a known phenotypic side effect of lowering ApoB levels. These results demonstrate a robust dose-dependent knockdown of ApoB by AAV-delivered shRNA in murine liver, thus providing an excellent candidate for development of RNAi-based gene therapy for the treatment of hypercholesterolemia.
2004-01-30 | Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy.
Inherited retinal and choroidal degenerations account for a significant portion of blindness in children and young adults. This article reviews the current status and future prospects for the treatment of these disorders. Current treatment strategies include nutritional intervention for gyrate atrophy of the choroid and retina with hyperornithinemia, abetalipoproteinemia, and Refsum's disease, as well as vitamin A supplementation for retinitis pigmentosa. Future therapeutic prospects include gene therapy for both recessive and dominant disease, secondary gene-based therapies, such as pharmaceutic gene product replacement and treatment with survival factors, anti-apoptotic agents, and calcium blockers, and, finally, stem cell therapy.
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