Kynamro (mipomersen) / Ionis, Kastle Therap - LARVOL DELTA

ESCRT-I complex enhances therapeutic efficacy of ASO drugs by regulating endosomal escape and glucose homeostasis. (PubMed, Mol Ther Nucleic Acids) - "Using human hepatocyte-derived cell models and FDA-approved ASO drugs inotersen and mipomersen, we demonstrate that suppression of specific ESCRT-I subunits, VPS23 and VPS28, markedly enhances ASO-mediated target silencing, whereas depletion of other subunits has minimal effect. Notably, this regulatory effect extends beyond ASOs to small interfering RNA (siRNA) therapeutics, indicating a broader role for ESCRT-I in RNA drug biology. Together, these findings uncover a metabolic-endosomal axis controlling nucleic acid drug efficacy and provide new mechanistic insight into intracellular determinants of RNA-based therapeutics."

Journal • TSG101

Absolute quantitative proteomics guides patient-stratified drug repurposing in clear cell and papillary renal cell carcinoma. (PubMed, bioRxiv) - "TPA index stratification nominated bempedoic acid (ACLY inhibitor) and tipiracil hydrochloride (TYMP inhibitor) as patient-stratified candidates for ccRCC, and auranofin (TXNRD1 inhibitor), bempedoic acid, and mipomersen (APOB-directed antisense oligonucleotide) for pRCC. By combining the TPA for absolute protein quantification with prescriptomics-guided drug-target mapping, we show that ccRCC and pRCC harbour distinct, individually stratifiable therapeutic vulnerabilities. These findings provide a proof-of-concept for proteomics-based treatment stratification in RCC and establish a scalable framework that, pending functional validation, could inform personalised therapeutic decision-making across RCC subtypes."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Papillary Renal Cell Carcinoma • Renal Cell Carcinoma • Solid Tumor • APOB

RNA editing: a modality for precise introduction of gain-of-function variants identified by human genetics (ASGCT 2026) - "However, prior oligonucleotide approaches to knock-down APOB, such as mipomersen, were limited by hepatotoxicity and hepatic steatosis...We developed RNA editing oligonucleotides to introduce protective variants observed in LDLR and APOB that may represent a new approach to treating ASCVD patients, especially those who do not reach their target lipid levels despite multiple lines of treatment. More broadly, there are many untapped opportunities to identify protective variants in human genetics, and to introduce RNA editing oligos that safely and effectively confer those benefits to broader populations."

Atherosclerosis • Cardiovascular • Dyslipidemia • Hepatology • Liver Failure • Metabolic Disorders • ADAR • APOB • LDLR

Development and validation of a novel ion-pair hydrophilic interaction liquid chromatography method for the separation and quantification of oligonucleotide therapeutics. (PubMed, SLAS Technol) - "This study provides an systematically optimized and validated analytical platform for the quality control of oligonucleotide medicines, particularly showing significant advantages in the separation of key impurities (e.g., n-1 sequences) for long-chain oligonucleotides (20-30 mer), laying a technical foundation for the precise analysis of hydrophilic biopolymers."

Journal

Rat and Rabbit Whole-Embryo Culture as a New Approach Method for Unlabeled Therapeutic Antisense Oligonucleotide Hazard Identification with No Requirement for Microinjection or Assisted Transfection. (PubMed, Nucleic Acid Ther) - "This study demonstrates that direct culture in media containing mipomersen, a 2'-O-methoxyethyl phosphorothioated antisense oligonucleotide (ASO), results in dose-responsive morphological changes in rat and rabbit whole-embryo culture (WEC)...WEC could complement or partially replace in vivo studies, reducing animal use and required test material amounts, while enabling robust developmental hazard identification for ONTs. This work informs future safety assessment strategies and regulatory guidance for ONTs."

Journal • Preclinical

Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions. (PubMed, Front Pharmacol) - "Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may..."

Journal • Review

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia. (ASH 2025) - "Twelve ASOs, Inotersen, Eplontersen,Olezarsen, Fomivirsen, Mipomersen, Tofersen, Nusinersen, Eteplirsen, Golodirsen, Viltolarsen,Casimersen (all FDA approved) and Volanesorsen (EMA approved) were evaluated in this study. With two ASOs, Fomivirsen and Eteplirsen, direct activation of platelets was noted. Studieswith additional ASOs revealed a novel immune mechanism involving ASO-PF4 complex formation andanti-PF4 antibody recognition that can plausibly mediate ASO-induced thrombocytopenia. These findingshighlight the key role PS linkages may play in ASO immunogenicity and provide a mechanistic frameworkfor risk mitigation in ASO drug design, supporting the safer development and broader application of ASOtherapeutics."

Hematological Disorders • Thrombocytopenia

Heat stress enhances VLDL secretion in chicken ovarian follicles to potentiate its impact on follicular cell survival and maturation. (PubMed, Poult Sci) - "HS (42°C) for 8 hr (HS8H) or HS3H and following recovery at 37°C to 16 hr (3H13R) upregulated PCNA and/or IL-1β expressions in granulosa (GC) and theca (TH) cells and augmented progesterone (P4) and estradiol (E2) production, respectively. Surprisingly, Lomitapide and Mipomersen rescued TH cell viability at HS8H and 8H8R in association with alleviated lipid, MDA, and ROS accumulations, whereas GCs exhibited improved viability at HS8H, but not at 8H8R and 3H13R in couple with worse depletion of neutral lipids and cholesterol, suggesting that HS operates at VLDL production to alter cellular lipid dynamics to potentiate cell death, while TH cells are more thermoresistant due to a proficient adaption in lipid disposal. In conclusion, HS enhances VLDL production in hierarchical follicles to augment its impacts on follicular cell fate, but routine secretion of VLDL is obligatory to sustain follicle maturation under normal conditions, in which TH cells are highly..."

Journal • IL1B • PCNA

Functional MTTP and apoB for VLDL secretion in chicken ovaries support small follicle development under heat stress. (PubMed, J Therm Biol) - "Lomitapide and Mipomersen augmented lipid accumulation, oxidative stress, inflammatory response, and exacerbated transient impairment of estradiol secretion and cell proliferation in SYFs under 3 h HS and after recovery, but failed to rescue cell viability despite relieved ER and proteostatic stress. In conclusion, routine secretion of VLDL by SYFs serves as an intrinsic mechanism to sustain cell viability and functions to support the whole program required for follicle development, while under HS, this mechanism provisionally rescues steroidogenesis and cell proliferation."

Journal • Inflammation • Targeted Protein Degradation • APOB • CASP3 • CASP7 • IL1B

Unlocking the potential: advancements and applications of gene therapy in severe disorders. (PubMed, Ann Med) - "To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atrophy, etc., rest for cancer, infectious diseases, and rare diseases. Additionally, advances in enhancing the immune system that would certainly lower the healthcare costs. This review highlights the translatory potential of gene therapy in revolutionizing the treatment landscape for severe disorders."

Journal • Review • Alzheimer's Disease • Autism Spectrum Disorder • Beta-Thalassemia • CNS Disorders • Cystic Fibrosis • Diabetes • Duchenne Muscular Dystrophy • Dyslipidemia • Familial Hypercholesterolemia • Gene Therapies • Genetic Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Oncology • Parkinson's Disease • Pulmonary Disease • Rare Diseases • Respiratory Diseases • Solid Tumor

NAVIGATING FAMILIAL HYPERCHOLESTEROLEMIA IN PREGNANCY - Cassandra Garraud (ACC 2025) - "Her LDL-C has been effectively managed with high intensity statin and ezetimibe which were discontinued during a prior pregnancy due to teratogenicity concerns...Recent cohort studies have not shown anomalies in those treated with hydrophilic statins and possible benefit in preeclampsia prevention, prompting the FDA to remove contraindication for use in selected patients in 2021.1 Other options for therapy during pregnancy include lifestyle, bile acid sequestrants, fenofibrates, omega-3 fatty acids, and mipomersen... Women of childbearing age with FH benefit from multidisciplinary care and individualized preconception counseling. Further studies with large clinical trials are needed to provide definitive safety data on statins."

Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Gynecology • Metabolic Disorders

COMPARATIVE EFFICACY, SAFETY, AND LONG-TERM OUTCOMES OF INJECTABLE CHOLESTEROL-LOWERING AGENTS: A NETWORK META-ANALYSIS OF ALIROCUMAB, EVOLOCUMAB, INCLISIRAN, AND MIPOMERSEN - Rakhshanda Khan (ACC 2025) - "Risk of bias was assessed using ROB 2.0. PCSK9 inhibitors, including Alirocumab, Evolocumab, Bococizumab, and Inclisiran, significantly reduced LDL-C levels, with reductions over 60%. PCSK9 inhibitors, particularly alirocumab and evolocumab, significantly reduce LDL-C and lower the risk of myocardial infarction, stroke, and revascularization. These agents provide a promising adjunct to statin therapy in high-risk patients with a favorable safety profile, supporting their role in improving long-term CV outcomes. Further research is needed on their long-term cost-effectiveness and clinical impact."

Retrospective data • Atherosclerosis • Cardiovascular • Myocardial Infarction

Impact on efficacy of target reduction of two FDA-approved ASO drugs by intracellular glucose levels in in vitro cell models. (PubMed, Mol Ther Nucleic Acids) - "Reducing intracellular glucose levels in HepG2 cells, either by knocking down the glucose transporter GLUT2 or by treating with the antidiabetic drug metformin, reversed the decreased silencing efficacy of inotersen and mipomersen. This study brings to light the first indication about the significant impact of intracellular glucose levels on the silencing efficacy of the FDA-approved ASO drugs in an in vitro model."

FDA event • Journal • Preclinical • Diabetes • Metabolic Disorders

Ovarian expression of functional MTTP and apoB for VLDL assembly and secretion in chickens. (PubMed, Poult Sci) - "Lomitapide and the ApoB-antisense oligonucleotide Mipomersen dose-dependently decreased MTTP activity and VLDL-apoB secretion from cultured follicular cells, while oleate addition or acute heat stress enhanced VLDL-apoB secretion. Ultrastructural images showed VLDL assembly and trafficking toward the secretion route. The findings support the notion that VLDL assembly and secretion within avian ovarian tissues functions as a protective mechanism against fuel and physical stressors to secure follicle development and/or nutritional quality control of yolk for embryo development."

Journal • Dyslipidemia • APOB

Antisense Oligonucleotides in Dyslipidemia Management: A Review of Clinical Trials. (PubMed, High Blood Press Cardiovasc Prev) - "The potential of antisense oligonucleotides (ASOs) to treat dyslipidemia and other disorders has attracted much interest. Several studies and clinical trials have been conducted on the safety and tolerability of ASOs for dyslipidemia. Although statins are the mainstay management of hypercholesterolemia, there is evidence from clinical trials that ASOs can even be more effective with little to no side effects. Novel therapeutic approaches such as antisense oligonucleotides (ASOs) offer tailored therapeutic alternatives. ASOs such as Mipomersen and Volanesorsen provide additional treatment options for patients with inherited lipid abnormalities by lowering certain atherogenic lipoproteins such as apo B and ApoC-III, respectively."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Repurposing lipid-lowering drugs on asthma and lung function: evidence from a genetic association analysis. (PubMed, J Transl Med) - "In conclusion, our findings suggest a likely causal relationship between asthma and lipid-lowering drugs. Moreover, there is compelling evidence indicating that lipid-lowering therapies could play a crucial role in the future management of asthma."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • ANGPTL3 • APOB • LDLR • PPARA

Therapeutic Potential of Lipoprotein(a) Inhibitors. (PubMed, Drugs) - "Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. (PubMed, BioDrugs) - "RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.]."

FDA event • Journal • Review • Amyloidosis • Amyotrophic Lateral Sclerosis • Cardiac Amyloidosis • CNS Disorders • Cytomegalovirus Infection • Duchenne Muscular Dystrophy • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Infectious Disease • Metabolic Disorders • Movement Disorders • Muscular Dystrophy • Rare Diseases

Inhibition of survivin by 2'-O-methyl phosphorothioate-modified steric-blocking antisense oligonucleotides. (PubMed, RSC Adv) - "To date, ten ASO drugs, which are capable of either inducing mRNA degradation via RNase H recruitment (fomivirsen, mipomersen, inotersen, volanesorsen and tofersen) or splice modulation (eteplirsen, nusinersen, golodirsen, viltolarsen and casimersen), have been approved by the regulatory agencies for market entry. Furthermore, western blot analysis confirmed that ASO-7 could significantly repress survivin production on protein level. Based on our preliminary results, we believe that ASO-7 could be a useful BIRC5 inhibitor for both research purpose and therapeutic development."

Journal • Oncology • BIRC5

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets. (PubMed, Lipids Health Dis) - "Currently, methods, such as mipomersen, lomitapide, and ANGPTL3 inhibitors, are used to reduce plasma cholesterol and triglyceride levels by regulating the lipidation, secretion, and metabolism of VLDL. Targeting VLDL represents an avenue for new lipid-lowering strategies. Interventions aimed at reducing VLDL production or enhancing VLDL metabolism, independent of the LDL receptor, hold promise for lowering cholesterol levels and providing therapeutic benefits beyond LDL in the management of ASCVD."

Journal • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • ANGPTL3

Traditional and novel non-statin lipid-lowering drugs. (PubMed, Indian Heart J) - "The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS...Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the..."

Journal • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Hepatology • Heterozygous Familial Hypercholesterolemia • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Pancreatitis • APOB • PCSK9

Trans-Biobank Mendelian Randomization Analyses Identify Distinct and Opposing Pathways in the Association of Lower Plasma Low-Density Lipoprotein-Cholesterol With Risk of Gallstone Disease (AHA 2023) - "Trial evidence suggests that lowering plasma LDL-cholesterol with bempedoic acid increases gallstone risk.Hypothesis: Different plasma LDL-cholesterol lowering pathways have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls)...We then performed clustered MR analyses followed by pathway analyses to identify distinct pathways in the association of lower plasma LDL-cholesterol with gallstone risk. Genetic mimics of statins were associated with lower gallstone risk, but genetic mimics of PCSK9 inhibitors, mipomersen and bile acid sequestrants were associated with higher gallstone risk... Genetic evidence suggests that different plasma LDL-cholesterol lowering pathways may have opposing effects on gallstone disease risk. Specifically,..."

Coronary Artery Disease • Dyslipidemia • Gastroenterology • Hepatology

Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives. (PubMed, Int J Environ Res Public Health) - "Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects...The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high."

Journal • Review • Atherosclerosis • Cardiovascular • CNS Disorders • Congestive Heart Failure • Dyslipidemia • Heart Failure • Metabolic Disorders • Peripheral Arterial Disease • Vascular Neurology • APOB

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a). (PubMed, Int J Mol Sci) - "Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results...Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule...The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off."

Journal • Review • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Heart Failure • Metabolic Disorders

Cardiovascular Disease Progression in Children With Homozygous Familial Hypercholesterolemia Despite Early Diagnosis on a Genetic Cascade Screening Program (AHA 2022) - "During follow-up all were on statin and ezetimibe therapies, and the mean final dose of atorvastatin was 56 ± 27 mg/d (n=10); and rosuvastatin, 26 ± 17 mg/d (n=3)...None were under LDL apheresis; 2 patients used mipomersen, 2 lomitapide, and 2 are currently using PCSK9 inhibitors... Despite early diagnosis and LDL-c reduction HoFH is still marked by an adverse and premature cardiovascular disease progression. Conventional lipid lowering therapies are not adequate to prevent ASCVD and VHD disease course."

Clinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heart Failure • Homozygous Familial Hypercholesterolemia • Metabolic Disorders