RARE DISEASE
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Synonyms: LAM
Synonyms: LAM
Synonyms: LAM
Drug discovery
5
drugs
With orphan designations
Overview
Lymphangioleiomyomatosis (LAM) is a rare, progressive multisystem neoplasm characterized by cystic lung destruction, lymphatic abnormalities, and renal angiomyolipomas. Driven by TSC1/TSC2 mutations causing mTOR pathway dysregulation, it predominantly affects women of reproductive age. Key features include dyspnea, recurrent pneumothoraces, chylous effusions, and progressive respiratory decline. Diagnosis relies on high-resolution CT, VEGF-D testing, and genetic evaluation. mTOR inhibitors (e.g., sirolimus) stabilize lung function and reduce complications [7].
Burden
50–80% experience pneumothorax (recurrent in most), 20–30% develop chylous complications [3][4][19].
Progressive lung function decline (FEV1 loss: 75–120 mL/year) [5][19].
10-year survival ~70%, with respiratory failure as the leading cause of mortality [3][4].
Significant quality-of-life impact due to dyspnea, fatigue, and frequent interventions [2][6].
Therapies
mTOR inhibitors: Sirolimus stabilizes lung function, reduces angiomyolipoma size, and resolves chylous effusions [2][6][10].
Pneumothorax management: Early pleurodesis (reduces recurrence from >70% to ~30%) [5][6].
Advanced care: Oxygen therapy, pulmonary rehabilitation, and lung transplantation (post-transplant survival ~12 years) [6][13].
Categories: rare genetic diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
677 drug discovery papers about Lymphangioleiomyomatosis, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
677 drug discovery papers about Lymphangioleiomyomatosis, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-30 | Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.
2026-06-26 | Decoding the Lymphangioleiomyomatosis (LAM) Niche Microenvironment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics.
Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-β signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.
2026-06-11 | Interleukin-8 and extracellular vesicles spread senescence in Lymphangioleiomyomatosis microenvironment.
The Senescence-Associated Secretory Phenotype (SASP), a hallmark of cellular senescence, is characterized by the presence of pro-inflammatory molecules, small Extracellular Vesicles (sEVs), and proteins that remodel the extracellular matrix. For this reason, SASP might contribute to the detrimental effects of senescence by promoting inflammation and parenchymal destruction. By controlling the translation of SASP factors, the mechanistic Target of Rapamycin (mTOR) is a central regulator of senescence. As a paradigm of senescence-driven lung impairment, we developed an in vitro model of Lymphangioleiomyomatosis (LAM), a pulmonary low-grade, destructive, metastasizing rare neoplasm. Primary LAM/TSC cells, that do not express the mTOR regulator tuberin, are senescent depending on mTOR constitutive activation and induce senescence in non-LAM pulmonary lung fibroblasts (PLFs) through their conditioned medium (CM), also inducing the secretion of the SASP factor Interleukin-8 (IL-8). Here, we demonstrate the possibility to counteract both the autocrine senescence in LAM/TSC cells and senescence induced on PLFs by inhibiting CXCR2, an IL-8 receptor that controls the senescent response to IL-8 stimuli, through the small molecule SB225002. With the aim to deepen the composition of LAM/TSC CM to identify the factors involved in senescence process, we also demonstrate that LAM/TSC cells release sEVs that contribute to senescence spreading on PLFs. Interestingly, IL-8 is enriched in the LAM/TSC sEVs samples compared to PLFs. Taken together, our results indicate the therapeutic potential to interfere with senescence spreading in lung microenvironment and suggest the employment of molecules targeting senescence as a worthy pharmacological approach for LAM.
2026-06-05 | The Leiomyoma-LAM Convergence: Nrf2-Keap1-Cullin 3 Axis Hijacking, Selenium-Dependent GPx Exhaustion, and a Three-Tier Metabolic Governance Strategy Across Estrogen-Sensitive and mTOR-Driven Smooth Muscle Proliferation
This paper proposes that uterine leiomyomas and lymphangioleiomyomatosis (LAM) converge on a shared molecular vulnerability: persistent activation of Nrf2 as a stress-buffer rather than a stress-resolver. In leiomyomas, defective neddylation of the Cullin 3-RING E3 ligase complex locks Nrf2 in constitutive activation, buffering tumor cells against ROS from chronic hypoxia and estrogen-driven CYP1B1 activity. In LAM, constitutive mTORC1 activation drives Warburg-like metabolic overload forcing compensatory Nrf2 hyperactivation. In both, the selenoprotein infrastructure — GPx1, GPx4, and TrxR — is progressively exhausted by chronic Nrf2-driven synthesis demand that selenium-insufficient individuals cannot meet. A three-tier governance strategy is proposed: GLP-1 receptor agonism (systemic metabolic stabilization), selenium and mineral cofactor optimization (restoring GPx and TrxR capacity), and methylene blue (mitochondrial electron shuttle reducing the ROS load on the restored selenoprotein system). All claims are hypothesis-level requiring prospective clinical confirmation.
2026-06-03 | The SIK Axis as a Progression Modifier in Lymphangioleiomyomatosis: Nutritional Antioxidant Reserve as a Determinant of Healthy Tissue Survival in the TSC2-Driven Lung Microenvironment
Lymphangioleiomyomatosis is a rare, progressive, almost exclusively female lung disease driven by loss-of-function mutations in TSC2 genes, resulting in constitutive mTORC1 hyperactivation. This paper proposes that the SIK axis applies as a progression modifier in LAM — the rate at which healthy surrounding lung parenchymal cells survive the oxidative microenvironment created by LAM nodules is determined in part by their own selenium-dependent, NRF2-dependent, and CoQ10-dependent antioxidant reserve capacity. All claims are hypothesis-level requiring prospective investigation.
2026-06-30 | Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.
2026-06-26 | Decoding the Lymphangioleiomyomatosis (LAM) Niche Microenvironment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics.
Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-β signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.
2026-06-11 | Interleukin-8 and extracellular vesicles spread senescence in Lymphangioleiomyomatosis microenvironment.
The Senescence-Associated Secretory Phenotype (SASP), a hallmark of cellular senescence, is characterized by the presence of pro-inflammatory molecules, small Extracellular Vesicles (sEVs), and proteins that remodel the extracellular matrix. For this reason, SASP might contribute to the detrimental effects of senescence by promoting inflammation and parenchymal destruction. By controlling the translation of SASP factors, the mechanistic Target of Rapamycin (mTOR) is a central regulator of senescence. As a paradigm of senescence-driven lung impairment, we developed an in vitro model of Lymphangioleiomyomatosis (LAM), a pulmonary low-grade, destructive, metastasizing rare neoplasm. Primary LAM/TSC cells, that do not express the mTOR regulator tuberin, are senescent depending on mTOR constitutive activation and induce senescence in non-LAM pulmonary lung fibroblasts (PLFs) through their conditioned medium (CM), also inducing the secretion of the SASP factor Interleukin-8 (IL-8). Here, we demonstrate the possibility to counteract both the autocrine senescence in LAM/TSC cells and senescence induced on PLFs by inhibiting CXCR2, an IL-8 receptor that controls the senescent response to IL-8 stimuli, through the small molecule SB225002. With the aim to deepen the composition of LAM/TSC CM to identify the factors involved in senescence process, we also demonstrate that LAM/TSC cells release sEVs that contribute to senescence spreading on PLFs. Interestingly, IL-8 is enriched in the LAM/TSC sEVs samples compared to PLFs. Taken together, our results indicate the therapeutic potential to interfere with senescence spreading in lung microenvironment and suggest the employment of molecules targeting senescence as a worthy pharmacological approach for LAM.
2026-06-05 | The Leiomyoma-LAM Convergence: Nrf2-Keap1-Cullin 3 Axis Hijacking, Selenium-Dependent GPx Exhaustion, and a Three-Tier Metabolic Governance Strategy Across Estrogen-Sensitive and mTOR-Driven Smooth Muscle Proliferation
This paper proposes that uterine leiomyomas and lymphangioleiomyomatosis (LAM) converge on a shared molecular vulnerability: persistent activation of Nrf2 as a stress-buffer rather than a stress-resolver. In leiomyomas, defective neddylation of the Cullin 3-RING E3 ligase complex locks Nrf2 in constitutive activation, buffering tumor cells against ROS from chronic hypoxia and estrogen-driven CYP1B1 activity. In LAM, constitutive mTORC1 activation drives Warburg-like metabolic overload forcing compensatory Nrf2 hyperactivation. In both, the selenoprotein infrastructure — GPx1, GPx4, and TrxR — is progressively exhausted by chronic Nrf2-driven synthesis demand that selenium-insufficient individuals cannot meet. A three-tier governance strategy is proposed: GLP-1 receptor agonism (systemic metabolic stabilization), selenium and mineral cofactor optimization (restoring GPx and TrxR capacity), and methylene blue (mitochondrial electron shuttle reducing the ROS load on the restored selenoprotein system). All claims are hypothesis-level requiring prospective clinical confirmation.
2026-06-03 | The SIK Axis as a Progression Modifier in Lymphangioleiomyomatosis: Nutritional Antioxidant Reserve as a Determinant of Healthy Tissue Survival in the TSC2-Driven Lung Microenvironment
Lymphangioleiomyomatosis is a rare, progressive, almost exclusively female lung disease driven by loss-of-function mutations in TSC2 genes, resulting in constitutive mTORC1 hyperactivation. This paper proposes that the SIK axis applies as a progression modifier in LAM — the rate at which healthy surrounding lung parenchymal cells survive the oxidative microenvironment created by LAM nodules is determined in part by their own selenium-dependent, NRF2-dependent, and CoQ10-dependent antioxidant reserve capacity. All claims are hypothesis-level requiring prospective investigation.
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Drug Discovery Landscape
5 orphan drug designations for Lymphangioleiomyomatosis, including 1 approved therapy.
5 orphan drug designations for Lymphangioleiomyomatosis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sirolimus | small molecules | EMA | 2016-07-14 | — | Maxia Strategies-Europe Limited |
sirolimus | small molecules | FDA | 2014-11-17 | — | Cote Orphan Consulting, LLC |
sirolimus | small molecules | FDA | 2014-06-25 | — | LAM Therapeutics, Inc. |
sirolimus [Rapamune] | small molecules | FDA | 2012-10-31 | 2015-05-28 | Pfizer, Inc. |
Quinacrine hydrochloride | small molecules | FDA | 1984-10-17 | — | Lyphomed, Inc. |
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