RARE DISEASE
Hereditary leiomyomatosis and renal cell cancer
Hereditary leiomyomatosis and renal cell cancer
Hereditary leiomyomatosis and renal cell cancer
Synonyms: Familial leiomyomatosis and renal cell cancer, Familial leiomyomatosis cutis et uteri, Familial leiomyomatosis with renal carcinoma, Familial multiple cutaneous leiomyomas, HLRCC, Hereditary leiomyomatosis, Hereditary leiomyomatosis with renal carcinoma, Hereditary multiple cutaneous leiomyomas, MCUL, Multiple cutaneous and uterine leiomyomas, Reed syndrome
Synonyms: Familial leiomyomatosis and renal cell cancer, Familial leiomyomatosis cutis et uteri, Familial leiomyomatosis with renal carcinoma, Familial multiple cutaneous leiomyomas, HLRCC, Hereditary leiomyomatosis, Hereditary leiomyomatosis with renal carcinoma, Hereditary multiple cutaneous leiomyomas, MCUL, Multiple cutaneous and uterine leiomyomas, Reed syndrome
Synonyms: Familial leiomyomatosis and renal cell cancer, Familial leiomyomatosis cutis et uteri, Familial leiomyomatosis with renal carcinoma, Familial multiple cutaneous leiomyomas, HLRCC, Hereditary leiomyomatosis, Hereditary leiomyomatosis with renal carcinoma, Hereditary multiple cutaneous leiomyomas, MCUL, Multiple cutaneous and uterine leiomyomas, Reed syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant disorder caused by germline FH mutations, disrupting the tricarboxylic acid cycle. It predisposes individuals to cutaneous/uterine leiomyomas and aggressive type 2 papillary renal cell carcinoma (RCC), with a 15–21% lifetime renal cancer risk [1][2][6]. Renal tumors often manifest in early adulthood (mean age 40–44) and exhibit rapid metastasis [4][7]. Surveillance includes annual abdominal MRI starting at age 8–10, while treatment prioritizes early surgical excision for localized disease [1][10].
Therapies
Localized RCC: Wide-margin nephrectomy ± retroperitoneal lymph node dissection [1][4]
Metastatic RCC: Bevacizumab + erlotinib (50% response rate) or clinical trials targeting HIF/KEAP1-NRF2 pathways [3][18]
Systemic options: Immune checkpoint inhibitors (nivolumab/ipilimumab) and PARP inhibitor trials [3][16][8]
Categories: rare genetic diseases, rare neoplastic diseases, rare renal diseases, rare skin diseases
Research Papers
209 drug discovery papers about Hereditary leiomyomatosis and renal cell cancer, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
209 drug discovery papers about Hereditary leiomyomatosis and renal cell cancer, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-30 | "In Silico / Computational Hypothesis" Repurposing Cysteamine as a DCAF15-Mediated Molecular Glue for Targeted Protein Degradation in Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)
Disclaimer / Legal Notice: Questo documento presenta un'ipotesi puramente teorica e computazionale generata in silico tramite inferenza topologica su ipergrafi di conoscenza. Questa proposta non è stata sottoposta a validazione in vitro, in vivo o clinica. Non costituisce in alcun modo un consiglio medico, una raccomandazione terapeutica o una prescrizione. Qualsiasi utilizzo clinico delle sostanze menzionate senza la supervisione di personale medico qualificato è severamente vietato e potenzialmente pericoloso.
2026-04-06 | Coexistence of Multiple Cutaneous Leiomyomas and Psoriasis Vulgaris: A Case Report and Review of Pathogenetic Insights.
The co-occurrence of multiple cutaneous leiomyomas (MCL) and psoriasis vulgaris (PV) is exceptionally rare, with no established pathophysiological link between these two conditions. We present a case of a 56-year-old woman with a 10-year history of widespread psoriatic plaques who presented with the concurrent development of multiple, firm, dark red papules and nodules. Histopathological examination confirmed the diagnosis of MCL, revealing interlacing bundles of spindle-shaped smooth muscle cells in the dermis, which were immunoreactive for smooth muscle actin and desmin. A separate biopsy from a psoriatic plaque showed characteristic features of PV. The patient was treated with a combination of thalidomide and tofacitinib, resulting in significant symptomatic and clinical improvement. This unique case highlights a potential, yet unexplored, interplay between smooth muscle proliferation and chronic inflammation, suggesting that shared immunogenetic mechanisms warrant further investigation. Clinicians should be aware of such unusual comorbidities when managing complex dermatological cases.
2026-04-03 | Abstract 253: Antitumor activity of PARP inhibitors in combination with Temozolomide in fumarate hydratase-deficient RCC.
Abstract Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare form of RCC associated with an aggressive clinical course. Despite the recent availability of therapeutic approaches active in FH-deficient RCC, most patients with advanced HLRCC die from their disease; identification of additional effective treatment strategies for these patients is, therefore, a therapeutic imperative. HLRCC is characterized by germline pathogenic variants in the fumarate hydratase (FH) gene, that encodes a key Tricarboxylic Acid (TCA) Cycle enzyme. Loss of FH activity leads to the accumulation of its substrate, fumarate. Excess fumarate serves as an oncometabolite and has been reported to suppress DNA damage repair. We evaluated the activity of PARP inhibitor-based combinations in preclinical models of HLRCC. The antitumor activity of two PARP inhibitors, Talazoparib and Niraparib, either as single agents or in combination with the alkylating chemotherapy agent temozolomide, was evaluated in several patient-derived HLRCC cell lines. In vitro viability assays demonstrated that both PARP inhibitors induced dose-dependent growth inhibition in HLRCC lines. The addition of temozolomide to either PARP inhibitor led to more pronounced reductions in cell proliferation across the HLRCC lines tested, compared to control single PARP inhibitors or temozolomide alone. At the molecular level, western blot analysis demonstrated that PARP inhibitors inhibited PARylation with concomitant upregulation of phosphorylated (ƴ) H2AX expression, and increased apoptosis. Furthermore, the effects on PARylation, ƴH2AX accumulation, and apoptosis were more pronounced in the PARP inhibitor/temozolomide combinations than with PARP inhibitors alone and were accompanied by substantial increases in cleaved PARP. These results demonstrate that PARP inhibitors have antitumor activity against HLRCC cells and that their activity is potentiated by the addition of the alkylating agent temozolomide. Additional in vitro and in vivo studies are ongoing to further define the activity of these combinations and to better understand the underlying molecular mechanisms. This study highlights the potential therapeutic utility of PARP inhibitor-based combinations in targeting DNA repair defects in HLRCC and provides the impetus for further exploration of this strategy. Citation Format: Sameer Issaq, Kylie Enten, Emily Hnath, Komal Rawal, Ramaprasad Srinivasan. Antitumor activity of PARP inhibitors in combination with Temozolomide in fumarate hydratase-deficient RCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 253.
2026-04-03 | Abstract 7328: EPR imaging of oxygen consumption driven by NQO1-activated compounds in FH-deficient renal tumors
Abstract Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC), characterized by mutations in the fumarate hydratase (FH) gene, are at risk for development of aggressive FH-deficient RCCs. FH-deficient tumor cells undergo a pronounced and irreversible metabolic shift to lactate fermentation due in part to loss and mutation of mitochondrial DNA. Fumarate accumulation in FH-deficient tumor cells leads to increased expression of NAD(P)H-quinone oxidoreductase 1 (NQO1) through activation of the NRF2 transcription factor. Although several therapeutic agents have shown promise in the treatment of FH-deficient RCC, clinical outcomes in patients remain unsatisfactory. In this study, we examined the mechanism and therapeutic efficacy of isobutyl-deoxynyboquinone (IB-DNQ), which undergoes futile redox cycling in the presence of NQO1 and oxygen, leading to sustained generation of the highly reactive and toxic superoxide anion. First, we found that patient-derived FH-deficient tumor cells exhibit minimal oxygen consumption in vitro, and EPR oxygen mapping of FH-deficient tumor xenografts in vivo revealed that tumor oxygen levels were elevated relative to other genetically defined in vivo models of RCC. Infusion of IB-DNQ in tumor-bearing animals resulted in rapid and robust non-mitochondrial oxygen consumption in FH-deficient tumor xenografts as measured by both EPR oxygen imaging and photoacoustic mapping of tumor hemoglobin saturation. Repeated doses of IB-DNQ resulted in reduced tumor growth rates. Metabolomic analyses revealed that IB-DNQ treatment strongly suppressed glycolysis and reduced cellular ATP levels by rapidly depleting NADH and NADPH in FH-deficient tumor cells. Finally, [1-13C]pyruvate hyperpolarized MR spectroscopy revealed decreased conversion of pyruvate to lactate in FH-deficient tumor xenografts following IB-DNQ treatment, providing a direct measurement of the impact of IB-DNQ on lactate fermentation in vivo. The combination of these in vivo imaging techniques and metabolite measurements demonstrate that NQO1-activated quinones can effectively target aerobic glycolysis in FH-deficient tumors which rely heavily on lactate fermentation for growth. Citation Format: Yuki Shibata, Shun Kishimoto, Ye Yang, Ming-Hui Wei, Julia Medina-Velazquez, Burchelle Blackman, Jeeva Munasinghe, Viraj Chegu, Vaishnavi S. Srirama, Tyler A. On, Nallathamby Devasahayam, Chandramouli V. Gadisetti, Jeffrey R. Brender, Murali C. Krishna, Daniel R. Crooks, William Marston Linehan. EPR imaging of oxygen consumption driven by NQO1-activated compounds in FH-deficient renal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7328.
2026-02-23 | A new inducible mouse model of FH loss.
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare autosomal dominant disorder that is characterized by the development of multiple cutaneous and uterine leiomyomas and predisposes individuals to an aggressive and highly metastatic form of Renal Cell Cancer (RCC).
antibodies
2026-03-06 | Case Report: A patient with metastatic fumarate hydratase-deficient renal cell carcinoma associated with leiomyomatosis: real-world clinical insights on systemic therapy and liver-directed SBRT.
Fumarate hydratase-deficient renal cell carcinoma is a rare type of renal cell carcinoma often associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. These tumors tend to exhibit an aggressive behavior and metastasize at an early stage. We describe the case of a 41-year-old woman of Chinese ethnicity who presented with progressive left flank pain and macroscopic hematuria. Computed tomography (CT) scan of the abdomen showed a large renal mass occupying the entire left kidney, left renal vein and inferior vena cava (IVC) tumor thrombus extension, left renal hilar lymphadenopathy, and indeterminate iliac bony and multiple large uterine fibroids. The patient underwent radical nephrectomy, caval thrombectomy and IVC reconstruction, total abdominal hysterectomy, and bilateral salpingo-oophorectomies. Histopathological examination revealed metastatic fumarate hydratase-deficient renal cell carcinoma associated with uterine leiomyomatosis with R1 resection margin at IVC. Owing to the lack of uniformly agreed guidelines for the management of this tumor, close surgical surveillance was advised. The patient subsequently developed postoperative liver metastases and sought self-funded medical care abroad. She subsequently received bevacizumab and erlotinib and achieved a favorable response. However, the patient experienced renal impairment with proteinuria following treatment, and the next cycle of systemic therapy was delayed. During this pause, we proceeded with stereotactic body radiation therapy (SBRT) to the remaining solitary liver metastasis. This case illustrates the practical challenges faced in treating fumarate hydratase-deficient renal cell carcinoma, including the lack of established systemic treatment guidelines and management of treatment-related adverse events. It highlights the value of integrating radiotherapy during interruptions in systemic therapy and the importance of multidisciplinary collaboration in this rare tumor.
2025-09-22 | Fumarate hydratase-deficient renal cell carcinoma: high intratumoral and peritumoral CD4-positive T cell infiltration density and high PD-L1 expression.
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) represents a rare and aggressive subtype of RCC, closely associated with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). The limited understanding of this disease presents significant clinical challenges in its management. To date, robust evidence supporting the efficacy of systemic therapies for FH-deficient RCC remains scarce. The objective of this study is to assemble a relatively large single-center cohort of FH-deficient RCC, focusing on clinical, pathological, and immune cell infiltration characteristics, particularly CD4-positive (CD4⁺) and CD8-positive (CD8⁺) T-cell infiltrates. This aims to enhance our understanding of FH-deficient RCC and provide evidence-based support for optimizing its systemic treatment strategies. We have retrospectively reviewed clinicopathologic and genetic prognostic data of patients operated on for renal tumor between January 2013 and June 2023 at Peking University First Hospital. Additionally, we employed multiplex immunofluorescence to evaluate the expression profiles of T cells within the tumor-infiltrating microenvironment of these patients. This study analyzed 27 patients (median age: 39.3 years; range 16-70; M: F = 14:13) with 31 renal tumors, including two multifocal cases. Histopathological evaluation revealed 25 high-grade tumors (WHO/ISUP G3-4) and two low-grade tumors (one with focal high-grade features and one entirely low-grade). Immunohistochemistry demonstrated universal strong 2SC positivity in all cases, while GATA3 expression (7 cases) was largely focal. Genomic profiling of 23 patients identified 18 germline and 3 somatic FH mutations, with two cases lacking FH alterations; MSI-L was detected in two tumors (others MSS). Multiplex immunofluorescence of 19 FH-deficient renal cell carcinomas revealed elevated PD-L1 expression (63.16% tumor cells) and distinct immune infiltration patterns: CD4+ T cell density exceeded CD8+ cells overall (1,125 vs. 336/mm², P = 0.005), with higher T cell accumulation at tumor margins (CD4+: 1,431/mm²; CD8+: 332/mm²) versus centers (CD4+: 911/mm²; CD8+: 164/mm²; PCD4=0.005, PCD8=0.017). CD4+ dominance persisted across all regions, suggesting a unique immunophenotypic signature in FH-deficient tumors. In FH-deficient RCC, only PD-L1 expression significantly predicted survival: PD-L1-positive patients had prolonged OS (median NR vs. 29.73 months in PD-L1-negative; P = 0.03). This analysis highlights the spatial heterogeneity of T-cell infiltration in FH-deficient RCCs and suggests a potential role for PD-L1-targeted therapies in this subset of tumors. These findings suggest a distinct spatial distribution of immune cell subsets within FH-deficient RCCs, with a pronounced enrichment of CD4-positive cells relative to CD8-positive cells, particularly at the tumor margin. This pattern may have important implications for understanding the tumor immune microenvironment and developing targeted immunotherapies for this subtype of RCC.
2024-08-19 | Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.
2024-03-07 | Case report: Response to immunotherapy and Association with FH gene in Hereditary Leiomyomatosis and Renal Cell Cancer Associated Renal Cell Carcinoma
Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) was a rare autosomal dominant syndrome caused by germline mutation in the fumarate hydratase (FH) gene; it manifestsas cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) had aggressive clinical courses, but there was no standardized therapy for advanced HLRCC-RCC. In this study, we described an aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126C>T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved partial response in immunotherapy and metastatic lesions had continued to benefit until now. A review of the literature identified 76 previously reported cases of HLRCC-related RCC in immunotherapy and 46 patients were enrolled in this study to analysis the correlation of FH gene and efficacy of immunotherapy. Our results indicated that the different mutations of FH germline gene were not affect efficacy of immunotherapy and immunotherapy could significantly improve the OS of HLRCC patients. Therefore, our study suggested that immunotherapy treatment was an effective therapeutic option for patients with HLRCC regardless of what form of FH germline mutation.
2023-04-01 | Data from Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma
<div>AbstractPurpose:<p>Fumarate hydratase–deficient renal cell carcinoma (FHRCC) is highly malignant, but the urgent need for effective treatment remains unmet. We aimed to analyze the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment at single-cell level.</p>Experimental Design:<p>Whole-exome sequencing and IHC staining analyses were performed in 30 advanced FHRCC patients. Single-cell RNA sequencing following ICI-based treatment was conducted in 4 patients. The clinical characteristics, therapeutic effect, and follow-up data were analyzed.</p>Results:<p>The median tumor mutation burden was only 0.14 mutations per megabase. IHC staining showed an immune-active tumor microenvironment characterized by extensive CD8<sup>+</sup> T-cell infiltration. ATM expression was inversely correlated with percentage of tumor-infiltrating CD8<sup>+</sup> T cells. Trajectory analysis indicated gradually upregulated exhausted markers and an increased apoptotic trend of CD8<sup>+</sup> T cells despite continuous exposure to ICI-based treatment. ICI-based treatment was associated with improved overall response rate (17.6% vs. 0%, <i>P</i> = 0.046) and disease control rate (DCR; 64.7% vs. 12.5%, <i>P</i> = 0.004) compared with tyrosine kinase inhibitor. Among patients with germline mutation, the ORR (16.7% vs. 0%, <i>P</i> = 0.086) and the DCR (66.7% vs. 14.3%, <i>P</i> = 0.011) were higher after ICI-based treatment.</p>Conclusions:<p>Immune infiltration is frequent in FHRCC. ICI-based treatment is a promising regimen, and treatment response depends on the functional status of tumor-infiltrating lymphocytes. ICI-based treatment cannot reverse the exhaustion of CD8<sup>+</sup> T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.</p></div>
gene therapies
2024-11-14 | Abstract B006: Rescuing expression of a tumor suppressor gene – restoring FH in Hereditary leiomyomatosis and renal cell carcinoma
Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a disorder characterized by the loss of fumarate hydratase (FH) activity, leading to the development of cutaneous leiomyomas, uterine leiomyomas, and aggressive early-onset type 2 papillary renal cell carcinoma. In HLRCC, the disease is driven by the somatic loss of the remaining functional FH allele in individuals carrying a germline pathogenic variant in one copy of the FH gene. The complete loss of FH activity disrupts the tricarboxylic acid (TCA) cycle, resulting in the accumulation of fumarate, which disrupts signaling pathways and contributes to the oncogenic phenotype. We recently identified a single nucleotide polymorphism (SNP) in an intronic region of the fumarate hydratase (FH) gene that leads to the loss of FH activity (Crooks et al., 2023). This SNP introduces a novel splice-acceptor site, resulting in the inclusion of an aberrant exon between wild-type exons 9 and 10. This ‘poison-like’ exon encodes a premature STOP codon, producing a nonfunctional truncated FH protein. Previous studies have shown that restoring FH activity can abrogate pathogenic behavior in patient-derived cells, highlighting the potential for therapeutic interventions targeting FH activity restoration. Our goal is to restore FH enzymatic activity by preventing the inclusion of this cryptic exon in carriers of this variant. To achieve this, we are exploring strategies to restore functional FH production by interfering with the inclusion of the pathogenic intron during splicing by removing the splice acceptor using CRISPR-Cas9 or base editing technologies. We tested these approaches by generating a reporter cell line that recapitulates the splicing pattern observed in patients, where expression of GFP depends on correct splicing between exon 9 and 10. We successfully identified antisense oligonucleotide (ASO) and single-guide RNA (sgRNA) sequences that restore GFP expression in our reporter cell lines. We are now evaluating the efficacy of these reagents in patient-derived cells. An alternative approach involves using synthetic RNA to restore FH expression. The expression of proteins from synthetic RNAs is a promising strategy for treating cancer and infectious diseases. We are currently investigating the efficiency of restoring FH activity through in-vitro transcribed (IVT) mRNA. This approach has the advantage of enabling FH function restoration in cells with mutations that are not amenable to antisense oligonucleotide (ASO) or gene editing techniques. This work serves as an avenue to investigate the application of nucleic acid therapies to restoring activity tumor suppressor genes in kidney cancer. Citation Format: Siddhardha S. Maligireddy, Mariana D. Mandler, Jodie C. Lunger, Christina M. Fitzsimmons, Daniel R. Crooks, Geetha M. Cawthon, Christopher J. Ricketts, Cathy D. Vocke, W. Marson Linehan, Pedro J. Batista. Rescuing expression of a tumor suppressor gene – restoring FH in Hereditary leiomyomatosis and renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B006.
2024-02-01 | DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection
Hereditary renal cell carcinoma (RCC) is caused by germline mutations in a subset of genes, including VHL, MET, FLCN, and FH. However, many familial RCC cases do not harbor mutations in the known predisposition genes. Using Whole Exome Sequencing, we identified two germline missense variants in the DCLRE1B/Apollo gene (ApolloN246I and ApolloY273H) in two unrelated families with several RCC cases. Apollo encodes an exonuclease involved in DNA Damage Response and Repair (DDRR) and telomere integrity. We characterized these two functions in the human renal epithelial cell line HKC8. The decrease or inhibition of Apollo expression sensitizes these cells to DNA interstrand crosslink damage (ICLs). HKC8 Apollo−/− cells appear defective in the DDRR and present an accumulation of telomere damage. Wild-type and mutated Apollo forms could interact with TRF2, a shelterin protein involved in telomere protection. However, only ApolloWT can rescue the telomere damage in HKC8 Apollo−/− cells. Our results strongly suggest that ApolloN246I and ApolloY273H are loss-of-function mutants that cause impaired telomere integrity and could lead to genomic instability. Altogether, our results suggest that mutations in Apollo could induce renal oncogenesis.
oligonucleotides
2025-09-02 | Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant cancer predisposition syndrome driven by the loss of fumarate hydratase (FH) activity. Recently, we identified a pathogenic variant in intron 9 of the FH gene that disrupts splicing by creating a novel splice acceptor site, resulting in the aberrant inclusion of a cryptic exon. Inclusion of the cryptic exon introduces a premature termination codon, leading to loss of FH activity. To restore FH expression, we sought to identify strategies to drive exclusion of the cryptic exon from the mature mRNA. To this end, we generated a minigene GFP reporter system that recapitulates the splicing defect observed in patients. We employed CRISPR-Cas9-mediated genome editing and antisense oligonucleotides (ASOs) to modulate splicing and demonstrated that both strategies can successfully promote skipping of the cryptic exon in a reporter cell line. Furthermore, we were able to show that ASOs can be used to shift the balance between the FH mRNA isoforms originated from the reference and the variant allele in patient-derived fibroblasts using ASOs. These findings support the potential for splicing modulation as a therapeutic approach for HLRCC-associated non-coding loss-of-function mutations in FH.
small molecules
2026-06-30 | "In Silico / Computational Hypothesis" Repurposing Cysteamine as a DCAF15-Mediated Molecular Glue for Targeted Protein Degradation in Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)
Disclaimer / Legal Notice: Questo documento presenta un'ipotesi puramente teorica e computazionale generata in silico tramite inferenza topologica su ipergrafi di conoscenza. Questa proposta non è stata sottoposta a validazione in vitro, in vivo o clinica. Non costituisce in alcun modo un consiglio medico, una raccomandazione terapeutica o una prescrizione. Qualsiasi utilizzo clinico delle sostanze menzionate senza la supervisione di personale medico qualificato è severamente vietato e potenzialmente pericoloso.
2026-04-06 | Coexistence of Multiple Cutaneous Leiomyomas and Psoriasis Vulgaris: A Case Report and Review of Pathogenetic Insights.
The co-occurrence of multiple cutaneous leiomyomas (MCL) and psoriasis vulgaris (PV) is exceptionally rare, with no established pathophysiological link between these two conditions. We present a case of a 56-year-old woman with a 10-year history of widespread psoriatic plaques who presented with the concurrent development of multiple, firm, dark red papules and nodules. Histopathological examination confirmed the diagnosis of MCL, revealing interlacing bundles of spindle-shaped smooth muscle cells in the dermis, which were immunoreactive for smooth muscle actin and desmin. A separate biopsy from a psoriatic plaque showed characteristic features of PV. The patient was treated with a combination of thalidomide and tofacitinib, resulting in significant symptomatic and clinical improvement. This unique case highlights a potential, yet unexplored, interplay between smooth muscle proliferation and chronic inflammation, suggesting that shared immunogenetic mechanisms warrant further investigation. Clinicians should be aware of such unusual comorbidities when managing complex dermatological cases.
2026-04-03 | Abstract 253: Antitumor activity of PARP inhibitors in combination with Temozolomide in fumarate hydratase-deficient RCC.
Abstract Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare form of RCC associated with an aggressive clinical course. Despite the recent availability of therapeutic approaches active in FH-deficient RCC, most patients with advanced HLRCC die from their disease; identification of additional effective treatment strategies for these patients is, therefore, a therapeutic imperative. HLRCC is characterized by germline pathogenic variants in the fumarate hydratase (FH) gene, that encodes a key Tricarboxylic Acid (TCA) Cycle enzyme. Loss of FH activity leads to the accumulation of its substrate, fumarate. Excess fumarate serves as an oncometabolite and has been reported to suppress DNA damage repair. We evaluated the activity of PARP inhibitor-based combinations in preclinical models of HLRCC. The antitumor activity of two PARP inhibitors, Talazoparib and Niraparib, either as single agents or in combination with the alkylating chemotherapy agent temozolomide, was evaluated in several patient-derived HLRCC cell lines. In vitro viability assays demonstrated that both PARP inhibitors induced dose-dependent growth inhibition in HLRCC lines. The addition of temozolomide to either PARP inhibitor led to more pronounced reductions in cell proliferation across the HLRCC lines tested, compared to control single PARP inhibitors or temozolomide alone. At the molecular level, western blot analysis demonstrated that PARP inhibitors inhibited PARylation with concomitant upregulation of phosphorylated (ƴ) H2AX expression, and increased apoptosis. Furthermore, the effects on PARylation, ƴH2AX accumulation, and apoptosis were more pronounced in the PARP inhibitor/temozolomide combinations than with PARP inhibitors alone and were accompanied by substantial increases in cleaved PARP. These results demonstrate that PARP inhibitors have antitumor activity against HLRCC cells and that their activity is potentiated by the addition of the alkylating agent temozolomide. Additional in vitro and in vivo studies are ongoing to further define the activity of these combinations and to better understand the underlying molecular mechanisms. This study highlights the potential therapeutic utility of PARP inhibitor-based combinations in targeting DNA repair defects in HLRCC and provides the impetus for further exploration of this strategy. Citation Format: Sameer Issaq, Kylie Enten, Emily Hnath, Komal Rawal, Ramaprasad Srinivasan. Antitumor activity of PARP inhibitors in combination with Temozolomide in fumarate hydratase-deficient RCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 253.
2026-04-03 | Abstract 7328: EPR imaging of oxygen consumption driven by NQO1-activated compounds in FH-deficient renal tumors
Abstract Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC), characterized by mutations in the fumarate hydratase (FH) gene, are at risk for development of aggressive FH-deficient RCCs. FH-deficient tumor cells undergo a pronounced and irreversible metabolic shift to lactate fermentation due in part to loss and mutation of mitochondrial DNA. Fumarate accumulation in FH-deficient tumor cells leads to increased expression of NAD(P)H-quinone oxidoreductase 1 (NQO1) through activation of the NRF2 transcription factor. Although several therapeutic agents have shown promise in the treatment of FH-deficient RCC, clinical outcomes in patients remain unsatisfactory. In this study, we examined the mechanism and therapeutic efficacy of isobutyl-deoxynyboquinone (IB-DNQ), which undergoes futile redox cycling in the presence of NQO1 and oxygen, leading to sustained generation of the highly reactive and toxic superoxide anion. First, we found that patient-derived FH-deficient tumor cells exhibit minimal oxygen consumption in vitro, and EPR oxygen mapping of FH-deficient tumor xenografts in vivo revealed that tumor oxygen levels were elevated relative to other genetically defined in vivo models of RCC. Infusion of IB-DNQ in tumor-bearing animals resulted in rapid and robust non-mitochondrial oxygen consumption in FH-deficient tumor xenografts as measured by both EPR oxygen imaging and photoacoustic mapping of tumor hemoglobin saturation. Repeated doses of IB-DNQ resulted in reduced tumor growth rates. Metabolomic analyses revealed that IB-DNQ treatment strongly suppressed glycolysis and reduced cellular ATP levels by rapidly depleting NADH and NADPH in FH-deficient tumor cells. Finally, [1-13C]pyruvate hyperpolarized MR spectroscopy revealed decreased conversion of pyruvate to lactate in FH-deficient tumor xenografts following IB-DNQ treatment, providing a direct measurement of the impact of IB-DNQ on lactate fermentation in vivo. The combination of these in vivo imaging techniques and metabolite measurements demonstrate that NQO1-activated quinones can effectively target aerobic glycolysis in FH-deficient tumors which rely heavily on lactate fermentation for growth. Citation Format: Yuki Shibata, Shun Kishimoto, Ye Yang, Ming-Hui Wei, Julia Medina-Velazquez, Burchelle Blackman, Jeeva Munasinghe, Viraj Chegu, Vaishnavi S. Srirama, Tyler A. On, Nallathamby Devasahayam, Chandramouli V. Gadisetti, Jeffrey R. Brender, Murali C. Krishna, Daniel R. Crooks, William Marston Linehan. EPR imaging of oxygen consumption driven by NQO1-activated compounds in FH-deficient renal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7328.
2026-02-23 | A new inducible mouse model of FH loss.
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare autosomal dominant disorder that is characterized by the development of multiple cutaneous and uterine leiomyomas and predisposes individuals to an aggressive and highly metastatic form of Renal Cell Cancer (RCC).
antibodies
2026-03-06 | Case Report: A patient with metastatic fumarate hydratase-deficient renal cell carcinoma associated with leiomyomatosis: real-world clinical insights on systemic therapy and liver-directed SBRT.
Fumarate hydratase-deficient renal cell carcinoma is a rare type of renal cell carcinoma often associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. These tumors tend to exhibit an aggressive behavior and metastasize at an early stage. We describe the case of a 41-year-old woman of Chinese ethnicity who presented with progressive left flank pain and macroscopic hematuria. Computed tomography (CT) scan of the abdomen showed a large renal mass occupying the entire left kidney, left renal vein and inferior vena cava (IVC) tumor thrombus extension, left renal hilar lymphadenopathy, and indeterminate iliac bony and multiple large uterine fibroids. The patient underwent radical nephrectomy, caval thrombectomy and IVC reconstruction, total abdominal hysterectomy, and bilateral salpingo-oophorectomies. Histopathological examination revealed metastatic fumarate hydratase-deficient renal cell carcinoma associated with uterine leiomyomatosis with R1 resection margin at IVC. Owing to the lack of uniformly agreed guidelines for the management of this tumor, close surgical surveillance was advised. The patient subsequently developed postoperative liver metastases and sought self-funded medical care abroad. She subsequently received bevacizumab and erlotinib and achieved a favorable response. However, the patient experienced renal impairment with proteinuria following treatment, and the next cycle of systemic therapy was delayed. During this pause, we proceeded with stereotactic body radiation therapy (SBRT) to the remaining solitary liver metastasis. This case illustrates the practical challenges faced in treating fumarate hydratase-deficient renal cell carcinoma, including the lack of established systemic treatment guidelines and management of treatment-related adverse events. It highlights the value of integrating radiotherapy during interruptions in systemic therapy and the importance of multidisciplinary collaboration in this rare tumor.
2025-09-22 | Fumarate hydratase-deficient renal cell carcinoma: high intratumoral and peritumoral CD4-positive T cell infiltration density and high PD-L1 expression.
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) represents a rare and aggressive subtype of RCC, closely associated with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). The limited understanding of this disease presents significant clinical challenges in its management. To date, robust evidence supporting the efficacy of systemic therapies for FH-deficient RCC remains scarce. The objective of this study is to assemble a relatively large single-center cohort of FH-deficient RCC, focusing on clinical, pathological, and immune cell infiltration characteristics, particularly CD4-positive (CD4⁺) and CD8-positive (CD8⁺) T-cell infiltrates. This aims to enhance our understanding of FH-deficient RCC and provide evidence-based support for optimizing its systemic treatment strategies. We have retrospectively reviewed clinicopathologic and genetic prognostic data of patients operated on for renal tumor between January 2013 and June 2023 at Peking University First Hospital. Additionally, we employed multiplex immunofluorescence to evaluate the expression profiles of T cells within the tumor-infiltrating microenvironment of these patients. This study analyzed 27 patients (median age: 39.3 years; range 16-70; M: F = 14:13) with 31 renal tumors, including two multifocal cases. Histopathological evaluation revealed 25 high-grade tumors (WHO/ISUP G3-4) and two low-grade tumors (one with focal high-grade features and one entirely low-grade). Immunohistochemistry demonstrated universal strong 2SC positivity in all cases, while GATA3 expression (7 cases) was largely focal. Genomic profiling of 23 patients identified 18 germline and 3 somatic FH mutations, with two cases lacking FH alterations; MSI-L was detected in two tumors (others MSS). Multiplex immunofluorescence of 19 FH-deficient renal cell carcinomas revealed elevated PD-L1 expression (63.16% tumor cells) and distinct immune infiltration patterns: CD4+ T cell density exceeded CD8+ cells overall (1,125 vs. 336/mm², P = 0.005), with higher T cell accumulation at tumor margins (CD4+: 1,431/mm²; CD8+: 332/mm²) versus centers (CD4+: 911/mm²; CD8+: 164/mm²; PCD4=0.005, PCD8=0.017). CD4+ dominance persisted across all regions, suggesting a unique immunophenotypic signature in FH-deficient tumors. In FH-deficient RCC, only PD-L1 expression significantly predicted survival: PD-L1-positive patients had prolonged OS (median NR vs. 29.73 months in PD-L1-negative; P = 0.03). This analysis highlights the spatial heterogeneity of T-cell infiltration in FH-deficient RCCs and suggests a potential role for PD-L1-targeted therapies in this subset of tumors. These findings suggest a distinct spatial distribution of immune cell subsets within FH-deficient RCCs, with a pronounced enrichment of CD4-positive cells relative to CD8-positive cells, particularly at the tumor margin. This pattern may have important implications for understanding the tumor immune microenvironment and developing targeted immunotherapies for this subtype of RCC.
2024-08-19 | Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.
2024-03-07 | Case report: Response to immunotherapy and Association with FH gene in Hereditary Leiomyomatosis and Renal Cell Cancer Associated Renal Cell Carcinoma
Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) was a rare autosomal dominant syndrome caused by germline mutation in the fumarate hydratase (FH) gene; it manifestsas cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) had aggressive clinical courses, but there was no standardized therapy for advanced HLRCC-RCC. In this study, we described an aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126C>T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved partial response in immunotherapy and metastatic lesions had continued to benefit until now. A review of the literature identified 76 previously reported cases of HLRCC-related RCC in immunotherapy and 46 patients were enrolled in this study to analysis the correlation of FH gene and efficacy of immunotherapy. Our results indicated that the different mutations of FH germline gene were not affect efficacy of immunotherapy and immunotherapy could significantly improve the OS of HLRCC patients. Therefore, our study suggested that immunotherapy treatment was an effective therapeutic option for patients with HLRCC regardless of what form of FH germline mutation.
2023-04-01 | Data from Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma
<div>AbstractPurpose:<p>Fumarate hydratase–deficient renal cell carcinoma (FHRCC) is highly malignant, but the urgent need for effective treatment remains unmet. We aimed to analyze the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment at single-cell level.</p>Experimental Design:<p>Whole-exome sequencing and IHC staining analyses were performed in 30 advanced FHRCC patients. Single-cell RNA sequencing following ICI-based treatment was conducted in 4 patients. The clinical characteristics, therapeutic effect, and follow-up data were analyzed.</p>Results:<p>The median tumor mutation burden was only 0.14 mutations per megabase. IHC staining showed an immune-active tumor microenvironment characterized by extensive CD8<sup>+</sup> T-cell infiltration. ATM expression was inversely correlated with percentage of tumor-infiltrating CD8<sup>+</sup> T cells. Trajectory analysis indicated gradually upregulated exhausted markers and an increased apoptotic trend of CD8<sup>+</sup> T cells despite continuous exposure to ICI-based treatment. ICI-based treatment was associated with improved overall response rate (17.6% vs. 0%, <i>P</i> = 0.046) and disease control rate (DCR; 64.7% vs. 12.5%, <i>P</i> = 0.004) compared with tyrosine kinase inhibitor. Among patients with germline mutation, the ORR (16.7% vs. 0%, <i>P</i> = 0.086) and the DCR (66.7% vs. 14.3%, <i>P</i> = 0.011) were higher after ICI-based treatment.</p>Conclusions:<p>Immune infiltration is frequent in FHRCC. ICI-based treatment is a promising regimen, and treatment response depends on the functional status of tumor-infiltrating lymphocytes. ICI-based treatment cannot reverse the exhaustion of CD8<sup>+</sup> T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.</p></div>
gene therapies
2024-11-14 | Abstract B006: Rescuing expression of a tumor suppressor gene – restoring FH in Hereditary leiomyomatosis and renal cell carcinoma
Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a disorder characterized by the loss of fumarate hydratase (FH) activity, leading to the development of cutaneous leiomyomas, uterine leiomyomas, and aggressive early-onset type 2 papillary renal cell carcinoma. In HLRCC, the disease is driven by the somatic loss of the remaining functional FH allele in individuals carrying a germline pathogenic variant in one copy of the FH gene. The complete loss of FH activity disrupts the tricarboxylic acid (TCA) cycle, resulting in the accumulation of fumarate, which disrupts signaling pathways and contributes to the oncogenic phenotype. We recently identified a single nucleotide polymorphism (SNP) in an intronic region of the fumarate hydratase (FH) gene that leads to the loss of FH activity (Crooks et al., 2023). This SNP introduces a novel splice-acceptor site, resulting in the inclusion of an aberrant exon between wild-type exons 9 and 10. This ‘poison-like’ exon encodes a premature STOP codon, producing a nonfunctional truncated FH protein. Previous studies have shown that restoring FH activity can abrogate pathogenic behavior in patient-derived cells, highlighting the potential for therapeutic interventions targeting FH activity restoration. Our goal is to restore FH enzymatic activity by preventing the inclusion of this cryptic exon in carriers of this variant. To achieve this, we are exploring strategies to restore functional FH production by interfering with the inclusion of the pathogenic intron during splicing by removing the splice acceptor using CRISPR-Cas9 or base editing technologies. We tested these approaches by generating a reporter cell line that recapitulates the splicing pattern observed in patients, where expression of GFP depends on correct splicing between exon 9 and 10. We successfully identified antisense oligonucleotide (ASO) and single-guide RNA (sgRNA) sequences that restore GFP expression in our reporter cell lines. We are now evaluating the efficacy of these reagents in patient-derived cells. An alternative approach involves using synthetic RNA to restore FH expression. The expression of proteins from synthetic RNAs is a promising strategy for treating cancer and infectious diseases. We are currently investigating the efficiency of restoring FH activity through in-vitro transcribed (IVT) mRNA. This approach has the advantage of enabling FH function restoration in cells with mutations that are not amenable to antisense oligonucleotide (ASO) or gene editing techniques. This work serves as an avenue to investigate the application of nucleic acid therapies to restoring activity tumor suppressor genes in kidney cancer. Citation Format: Siddhardha S. Maligireddy, Mariana D. Mandler, Jodie C. Lunger, Christina M. Fitzsimmons, Daniel R. Crooks, Geetha M. Cawthon, Christopher J. Ricketts, Cathy D. Vocke, W. Marson Linehan, Pedro J. Batista. Rescuing expression of a tumor suppressor gene – restoring FH in Hereditary leiomyomatosis and renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B006.
2024-02-01 | DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection
Hereditary renal cell carcinoma (RCC) is caused by germline mutations in a subset of genes, including VHL, MET, FLCN, and FH. However, many familial RCC cases do not harbor mutations in the known predisposition genes. Using Whole Exome Sequencing, we identified two germline missense variants in the DCLRE1B/Apollo gene (ApolloN246I and ApolloY273H) in two unrelated families with several RCC cases. Apollo encodes an exonuclease involved in DNA Damage Response and Repair (DDRR) and telomere integrity. We characterized these two functions in the human renal epithelial cell line HKC8. The decrease or inhibition of Apollo expression sensitizes these cells to DNA interstrand crosslink damage (ICLs). HKC8 Apollo−/− cells appear defective in the DDRR and present an accumulation of telomere damage. Wild-type and mutated Apollo forms could interact with TRF2, a shelterin protein involved in telomere protection. However, only ApolloWT can rescue the telomere damage in HKC8 Apollo−/− cells. Our results strongly suggest that ApolloN246I and ApolloY273H are loss-of-function mutants that cause impaired telomere integrity and could lead to genomic instability. Altogether, our results suggest that mutations in Apollo could induce renal oncogenesis.
oligonucleotides
2025-09-02 | Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant cancer predisposition syndrome driven by the loss of fumarate hydratase (FH) activity. Recently, we identified a pathogenic variant in intron 9 of the FH gene that disrupts splicing by creating a novel splice acceptor site, resulting in the aberrant inclusion of a cryptic exon. Inclusion of the cryptic exon introduces a premature termination codon, leading to loss of FH activity. To restore FH expression, we sought to identify strategies to drive exclusion of the cryptic exon from the mature mRNA. To this end, we generated a minigene GFP reporter system that recapitulates the splicing defect observed in patients. We employed CRISPR-Cas9-mediated genome editing and antisense oligonucleotides (ASOs) to modulate splicing and demonstrated that both strategies can successfully promote skipping of the cryptic exon in a reporter cell line. Furthermore, we were able to show that ASOs can be used to shift the balance between the FH mRNA isoforms originated from the reference and the variant allele in patient-derived fibroblasts using ASOs. These findings support the potential for splicing modulation as a therapeutic approach for HLRCC-associated non-coding loss-of-function mutations in FH.
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