Abstract
Heterozygous familial hypercholesterolemia is a common genetic disorder characterized by lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. YOLT-101 is an investigational in vivo gene therapy that uses adenine base-editing technology, delivered via GalNAc-modified lipid nanoparticles to inactivate PCSK9 and achieve sustained LDL-C reduction. Here we report interim results from an ongoing clinical trial evaluating primary (safety and tolerability) and secondary (lowering of PCSK9 and LDL-C levels) outcomes of a single intravenous dose of YOLT-101 in adults with heterozygous familial hypercholesterolemia and uncontrolled LDL-C. Six participants (three men and three women) received escalating doses of YOLT-101 (0.2, 0.4 or 0.6 mg kg−1). No grade ≥3 adverse events occurred. Transient and self-limited infusion-related reactions and elevations in liver enzymes were the most common adverse events. A single infusion of YOLT-101 induced dose-dependent and durable reductions in circulating PCSK9 and LDL-C, with sustained reductions of 74.4% and 52.3%, respectively, at 24 weeks in the 0.6 mg kg−1 cohort (n = 3), demonstrating promise for future clinical development. ClinicalTrials.gov registration: NCT06458010.
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Data availability
The NGS data generated in this Article can be found in the National Center for Biotechnology Information’s Sequence Read Archive (accession number PRJNA1414270). The minimum datasets necessary to interpret, verify and extend the findings of this study, including Digenome-seq, GUIDE-seq, CIRCLE-seq, hybrid capture sequencing, whole-genome sequencing and RNA-seq data, are accessible through this repository. De-identified individual participant data from the clinical trial are available without restrictions from the corresponding author, from 6 to 36 months after article publication. Requests will be responded to within 60 days. Source data are provided with this paper.
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Acknowledgements
We thank all the patients and their families for their participation in the present study and the staff at Ren Ji Hopital for their contributions to the care of the patients. This trial was sponsored by YolTech Therapeutics. The sponsor was involved in clinical protocol design, data analysis and YOLT-101 production. We appreciate the support of grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2025ZD0552204 to Q.X.), a subproject of the 2025 Key Technology Research and Development Program of the Shanghai Science and Technology Commission (grant no. 25J32800104 to P.W.), the National Natural Science Foundation of China (grant no. 82588101 to Q.X. and grant no. 82570698&82300658 to T.Y.), the Shanghai Central Guidance for Local Science and Technology Development Fund (grant no. YDZX20243100002002 to Q.X.), the Shanghai Science and Technology Innovation Action Plan - Special Program for Medical Innovation Research (grant no. 22Y21900400 to Q.X.), the National Key R&D Program of China (grant no. 2023YFC3403401 to Y.W.), the National Natural Science Foundation of China (grant no. 82270125 to Y.W.), the project of Shanghai Municipal Science and Technology Commission (grant no. 23HC1400400 to Y.W.) and the National Program for Support of Top-Notch Young Professionals (Y.W.).
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Contributions
Z.J.W., Y.W., T.Y. and Q.X. designed and led the study. Q.X. was site principal investigator. P.W., S.T., D.L., Y. Lu and M.L. conducted the study and analyzed data with the help of L.X., Y.J. and J.L. X.M., Y. Liu and W.Y. were involved in patient care, testing and data presentation. P.W., S.T., D.L., Y. Lu, M.L., M.O., Z.J.W., Y.W., T.H. and Q.X. wrote the manuscript. All authors contributed to the manuscript and approved its final version.
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Competing interests
L.X., X.M., Y. Liu and W.Y. are employees of YolTech Therapeutics. M.O is a member of the advisory board for YolTech Therapeutics. Y. Lu, Z.J.W. and Y.W. are cofounders of YolTech Therapeutics. YOLT-101, the investigational product used in this study, is developed by YolTech Therapeutics. These relationships did not influence the study design, data collection, analysis or interpretation. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Mechanism of YOLT-101 in reducing PCSK9 and lowering LDL-C.
a, The structure of YOLT-101, which is administered via intravenous infusion. Its carrier system is a GalNAc-modified lipid nanoparticle (LNP) system, designed for enhanced targeted delivery to hepatocytes. The active components, including adenine base editor (hpABE5) mRNA and single-guide RNA (sgRNA), are encapsulated within the LNP and specifically target the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in the liver. b, The dual-targeting mechanism by which YOLT-101 is delivered to hepatocytes. Following administration and entry into the circulation, the LNPs are opsonized by apolipoprotein E (ApoE). The LNPs, which contain the active components, bind to the low-density lipoprotein receptor (LDLR) on hepatocyte surfaces via ApoE, facilitating receptor-mediated endocytosis. Simultaneously, the LNPs are directed to hepatocytes through GalNAc, which specifically targets the asialoglycoprotein receptor (ASGPR) on hepatocyte surfaces, enhancing delivery via an LDLR-independent pathway. c, The precise base editing process. Upon entering the hepatocyte, sgRNA guides the hpABE5 ribonucleoprotein complex to the target site in the PCSK9 gene. The complex catalyzes the deamination of adenine (A) to inosine (I), which is then processed by the cell’s DNA repair machinery as guanine (G). This results in a precise A-to-G substitution, disrupting the normal splicing of PCSK9 mRNA and introducing a frameshift mutation that inactivates the PCSK9 gene, effectively silencing its expression. d, The reduction in PCSK9 expression leads to enhanced recycling of the LDLR. With less PCSK9 available to degrade LDLR, the receptors remain functional and are efficiently recycled, increasing LDL-C uptake into hepatocytes. This process lowers circulating LDL-C levels, thereby resulting in the therapeutic effect of YOLT-101.
Extended Data Fig. 2 Assessment of off-target editing in primary human hepatocytes.
a, The representative dose-response curve for on-target editing in primary human hepatocytes (PHH) (mean ± standard deviation for each site, n = 3 treated and 3 untreated biological replicates). b, A Venn diagram illustrating the number of potential off-target sites identified for YOLT-101 across three different methods: CIRCLE-seq, Digenome-seq, and GUIDE-seq. c, Candidate sites for gRNA-dependent DNA editing identified by CIRCLE-seq (left), Digenome-seq (middle), and GUIDE-seq (right). Overlapping sites are marked with identical numbering. d, The net A-to-G editing at on-target and 62 candidate off-target sites in primary human hepatocytes of three donors following YOLT-101 genome editing at the EC90 dose or left untreated. The grey boxes indicate values below the detection limit of NGS (0.1%)(for each donor, n = 3 treated and 3 untreated samples). e, The variant allele frequency of genome-level A-to-G (left, A-to-G mutation at the sense strand of reference genome GRChg38) and T-to-C (right, A-to-G mutation at the antisense strand of reference genome GRChg38) mutations in the DNA of primary human hepatocytes observed in the untreated control (NC) and YOLT-101 treated groups (n = 1 treated and 1 untreated samples). No significant difference in A to G (P-value = 0.1589, one-sided Wilcoxon-Mann-Whitney test) or T to C (P-value = 0.1943, one-sided Wilcoxon-Mann-Whitney test) mutations was observed between the treated and untreated primary human hepatocytes). f, The variant allele frequency of transcriptome-wide A-to-I mutations in the RNA of primary human hepatocytes observed in the NC and YOLT-101 groups (n = 3 treated and 3 untreated biological replicates). Following the analysis of SNP data, no significant additional A to I RNA edits (P-value = 0.1385, one-sided Wilcoxon-Mann-Whitney test) were detected in the primary human hepatocytes treated with YOLT-101 at the EC90 dose when compared to the untreated control group. g, DNA structural variant events in primary human hepatocytes detected by PacBio, including insertions, deletions, duplications, inversions, and translocations (n = 1 treated and 1 untreated samples).
Extended Data Fig. 3 Biochemical, hematological, and coagulation indicators in HeFH patients following YOLT-101 administration.
a-i, Time-course changes in key clinical biomarkers across three dosing groups: 0.2 mg/kg (orange n = 1), 0.4 mg/kg (blue n = 2), and 0.6 mg/kg (green n = 3). a, Alanine aminotransferase (ALT) levels. b, Aspartate aminotransferase (AST) levels. c, Total bilirubin (TBIL) levels. d, White blood cell (WBC) counts. e, Platelet counts. f, Hemoglobin (Hb) levels. g, Prothrombin time (PT). h, Activated partial thromboplastin time (APTT). i, Creatinine (CREA) levels. Data points represent the mean ± standard deviation for each group, and red dashed lines indicate the upper limit of normal (ULN) and lower limit of normal (LLN) for each parameter. To convert values for total bilirubin to micromoles per liter, multiply by 0.05848. To convert values for creatinine to micromoles per liter, multiply by 0.01131.
Extended Data Fig. 4 Inflammatory and immune biomarkers in HeFH patients following YOLT-101 administration.
a-h, Time-course changes in inflammatory and immune biomarkers across three dosing groups: 0.2 mg/kg (orange n = 1), 0.4 mg/kg (blue n = 2), and 0.6 mg/kg (green n = 3). a, Interleukin-6 (IL-6). b, Interleukin-1 beta (IL-1β). c, Interleukin-8 (IL-8). d, C-reactive protein (CRP). e, Complement component 3 (C3). f, Complement component 4 (C4). g, Tumor necrosis factor (TNF). h, Interferon-gamma (IFN-γ). Data points represent the mean ± standard deviation for each group, and red dashed lines indicate the upper limit of normal (ULN) and lower limit of normal (LLN) for each parameter.
Extended Data Fig. 5 Lymphocyte subpopulations in HeFH patients following YOLT-101 administration.
a-d, Time-course changes in various lymphocyte subpopulations across three dosing groups: 0.2 mg/kg (orange n = 1), 0.4 mg/kg (blue n = 2), and 0.6 mg/kg (green n = 3). a, B cells. b, Natural killer (NK) cells. c, T helper (Th) cells. d, T suppressor (Ts) cells. Data points represent the mean ± standard deviation for each group, and red dashed lines indicate the upper limit of normal (ULN) and lower limit of normal (LLN) for each parameter.
Extended Data Fig. 6 PCSK9 levels in all enrolled participants following YOLT-101 administration.
a, Absolute PCSK9 levels over time in all 6 patients treated with YOLT-101. b, Percentage changes in PCSK9 levels over time from baseline in all 6 patients treated with YOLT-101. Data are presented as mean ± standard deviation (SD) or individual patient values, as indicated.
Extended Data Fig. 7 LDL-C levels in all enrolled participants following YOLT-101 administration.
a, Absolute LDL-C levels over time in all 6 patients treated with YOLT-101. b, Percentage changes in LDL-C levels over time from baseline in all 6 patients treated with YOLT-101. Data are presented as mean ± standard deviation (SD), as indicated. To convert values for cholesterol to milligrams per deciliter, multiply by 38.67.
Extended Data Fig. 8 Study timeline for YOLT-101 administration and follow-up.
a, Main study period. b, Long-term follow-up period.
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Wan, P., Tang, S., Lin, D. et al. In vivo base editing gene therapy for heterozygous familial hypercholesterolemia: a phase 1 trial. Nat Med 32, 1045–1051 (2026). https://doi.org/10.1038/s41591-026-04254-4
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DOI: https://doi.org/10.1038/s41591-026-04254-4
