RARE DISEASE
Hereditary pulmonary alveolar proteinosis
Hereditary pulmonary alveolar proteinosis
Hereditary pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary pulmonary alveolar proteinosis (hPAP) is a rare genetic interstitial lung disease caused by mutations in CSF2RA or CSF2RB, disrupting GM-CSF receptor signaling and impairing alveolar macrophage surfactant clearance. It presents insidiously with dyspnea, hypoxemia, and cough, often in childhood. Diagnosis relies on genetic testing, bronchoalveolar lavage showing PAS-positive material, and absence of GM-CSF autoantibodies. Whole-lung lavage (WLL) remains the primary treatment, though emerging gene therapies show promise [1][3][8][10].
Categories: rare genetic diseases, rare immunological diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
107 drug discovery papers about Hereditary pulmonary alveolar proteinosis, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
107 drug discovery papers about Hereditary pulmonary alveolar proteinosis, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-10 | Lung Transplantation for Pulmonary Alveolar Proteinosis - a Retrospective International Multi-Center Analysis.
Pulmonary alveolar proteinosis (PAP) is a rare disease. Only a small number of case reports describing lung transplantation (LTx) as a treatment option for PAP have been published. Due to this limited evidence, current guidelines on LTx for PAP remain vague. To address this gap, we collected cases of LTx for PAP worldwide. 214 centers were approached to contribute any cases of LTx performed for PAP. Re-transplantations and multi-organ transplantations were excluded. Patients were divided into two groups based on the presence of PAP recurrence after LTx. Time-to-event-analyses were performed by Kaplan-Meier curves and cox-proportional-hazards-modelling was performed with PAP recurrence as a time-dependent covariate. At a response rate of 64%, 31 centers contributed 63 patients. Most had primary PAP (n=20; 39.2%). 6 patients with secondary PAP were identified (11.8%), while 7 (13.7%) had congenital and 18 (35.3%) unclassified PAP. Etiology was not specified in 12. Patients underwent transplantation at a median 11 years (IQR 3-17) after initial diagnosis. Nine patients (15%) developed PAP recurrence after LTx. No significant difference was found regarding patient characteristics between the patients with versus without recurrence. Freedom from recurrence was 96.2% (1y), 83.5% (5y) and 70.1% (10y) post-LTx. PAP recurrence as time-dependent covariate was not significantly associated with graft loss (HR=1.88, 95%CI:0.51-6.91, p=0.342) in a cox-proportional-hazards-model. LTx provides excellent perioperative and long-term outcomes for patients with end-stage PAP and should be recommended in treatment guidelines. Although recurrence of PAP occurs in approximately 15% of cases, overall survival appeared unaffected in our limited dataset.
2026-06-01 | B95-10 A First-in-human Study of Pulmonary Macrophage Transplantation Therapy of Hereditary Pulmonary Alveolar Proteinosis
Abstract Background CSF2RA mutations cause hereditary alveolar proteinosis (hPAP), a surfactant accumulation disorder, by disrupting GM-CSF signaling to alveolar macrophages (AMs), which require GM-CSF to maintain normal surfactant clearance and other functions and regulation of AM population size (in mice). Pulmonary macrophage transplantation (PMT) is a promising therapeutic approach for hPAP based on genetically restoring GM-CSF signaling to AMs. Preclinical mouse studies demonstrated PMT was safe and that efficacy was proportional to cell dose and time allowed for treatment development. Objectives: This study evaluated the feasibility, tolerability, safety, and efficacy of CSF2RA gene/PMT therapy in a 22-year-old woman with hPAP caused by biallelic CSF2RA mutations (G174R, gene deletion). Methods Autologous, gene-corrected macrophages (cells) were prepared from bone marrow progenitors by transduction with a self-inactivating, 3rd generation lentiviral vector expressing a CSF2RA transgene, followed by ex vivo cell expansion, differentiation into macrophages, and cryopreservation until administration. The cell dose (11 million cells/kg ideal body weight) was based on mouse toxicology results and was equivalent in size to 16% of the adult human AM population. Cells were thawed, formulated in saline, tested, and instilled bronchoscopically into individual lung segments in two doses. The first was a split-dose delivered into 1, 4, then 14 segments sequentially at 2-month intervals. The second dose involved delivery into all 19 segments 16 months later. The rationale for this administration scheme was our focus on safety and because the achievable gene-correction rate had been 100% in mouse cells but only ∼50% in human cells. Results Two separate cell lots comprised 131% and 104% of the targeted production amount and met all lot-release criteria. Administration was nominal and not accompanied by bronchospasm, serious adverse events, or antibody responses to either the vector or transgene product. Evidence of biological efficacy included detection of vector DNA and transgene product in AMs, reduced bronchoalveolar lavage turbidity, and detection of morphologically normal AMs. Evidence of clinical efficacy included improvement in body mass index, DLCO%, exercise capacity, minor improvement in computed tomography, and reduction in surfactant burden (total pulmonary surfactant level) as demonstrated by time-dependent reduction in the ‘barrier signal’ from hyperpolarized 129Xe magnetic resonance imaging (MRI) (Figure). Conclusions Results show PMT therapy of hPAP was feasible, tolerable, safe, and efficacious. Clinical efficacy was proportional to cell dose and treatment duration and developed over 26 months of follow-up. Interestingly, hyperpolarized 129Xe MRI imaging was more sensitive in measuring surfactant burden than computed tomography. This abstract is funded by: NIH R33 HL156888
2025-09-27 | Pulmonary Alveolar Proteinosis: a 3-country cohort study Greece, Türkiye, Cyprus
Background: Pulmonary Alveolar Proteinosis (PAP) is a rare disease with inappropriate accumulation of surfactant in alveoli. Aim to characterize 3 cohorts in 3 Mediterranean neighbors (Greece, Türkiye, Cyprus) the last 20 years. Methods: Epidemiological, clinical and functional data were analyzed Results: Included are 124 patients: 32% Greece, 65% Türkiye, 3% Cyprus; 109 (88%) autoimmune PAP (aPAP), 13 (11%) secondary and 1 (1%) congenital; 49% male, 65% ever-smokers, followed-up 39 (16-83) months. At diagnosis median (IQR) age 39 (30-47) years, %-predicted FVC 77 (64-91), DLCO 55 (37-68),14% in LTOT. 7% had died. Whole lung lavage (WLL) in 51%, history of inhaled-GMCSF (sargramostim or molgramostim) in 44%. During FU, patients ameliorated [FVC% (p=0.007), DLCO% (p=0.001)]. Baseline characteristics of the three cohorts were similar. Significant differences were: WLL in Türkiye 64% vs 26% in Greece and Cyprus (p<0.001) and history of i-GMCSF as sole therapy 51% in Greece vs 9% in Türkiye (p<0.001). Deceased patients were more likely to be older (p=0.009), have secondary PAP (p<0.001), more comorbidities (p=0.035), higher oxygen-needs (p<0.001), worse functional status at FU (p=0.001) and complicated by pulmonary fibrosis (p<0.001). Patients who received i-GMCSF as sole therapy had no significant differences regarding age, disease severity or outcome compared to those with a history of WLL alone or in combination with i-GMCSF. Conclusion: In Türkiye WLL was the mainstay of treatment, while in Greece i-GM-CSF. Secondary PAP, age and pulmonary fibrosis negatively influenced prognosis. i-GMCSF as the sole therapy was not inferior to WLL or WLL followed by i-GMCSF irrespective of the severity of patients.
2026-07-10 | Lung Transplantation for Pulmonary Alveolar Proteinosis - a Retrospective International Multi-Center Analysis.
Pulmonary alveolar proteinosis (PAP) is a rare disease. Only a small number of case reports describing lung transplantation (LTx) as a treatment option for PAP have been published. Due to this limited evidence, current guidelines on LTx for PAP remain vague. To address this gap, we collected cases of LTx for PAP worldwide. 214 centers were approached to contribute any cases of LTx performed for PAP. Re-transplantations and multi-organ transplantations were excluded. Patients were divided into two groups based on the presence of PAP recurrence after LTx. Time-to-event-analyses were performed by Kaplan-Meier curves and cox-proportional-hazards-modelling was performed with PAP recurrence as a time-dependent covariate. At a response rate of 64%, 31 centers contributed 63 patients. Most had primary PAP (n=20; 39.2%). 6 patients with secondary PAP were identified (11.8%), while 7 (13.7%) had congenital and 18 (35.3%) unclassified PAP. Etiology was not specified in 12. Patients underwent transplantation at a median 11 years (IQR 3-17) after initial diagnosis. Nine patients (15%) developed PAP recurrence after LTx. No significant difference was found regarding patient characteristics between the patients with versus without recurrence. Freedom from recurrence was 96.2% (1y), 83.5% (5y) and 70.1% (10y) post-LTx. PAP recurrence as time-dependent covariate was not significantly associated with graft loss (HR=1.88, 95%CI:0.51-6.91, p=0.342) in a cox-proportional-hazards-model. LTx provides excellent perioperative and long-term outcomes for patients with end-stage PAP and should be recommended in treatment guidelines. Although recurrence of PAP occurs in approximately 15% of cases, overall survival appeared unaffected in our limited dataset.
2026-06-01 | B95-10 A First-in-human Study of Pulmonary Macrophage Transplantation Therapy of Hereditary Pulmonary Alveolar Proteinosis
Abstract Background CSF2RA mutations cause hereditary alveolar proteinosis (hPAP), a surfactant accumulation disorder, by disrupting GM-CSF signaling to alveolar macrophages (AMs), which require GM-CSF to maintain normal surfactant clearance and other functions and regulation of AM population size (in mice). Pulmonary macrophage transplantation (PMT) is a promising therapeutic approach for hPAP based on genetically restoring GM-CSF signaling to AMs. Preclinical mouse studies demonstrated PMT was safe and that efficacy was proportional to cell dose and time allowed for treatment development. Objectives: This study evaluated the feasibility, tolerability, safety, and efficacy of CSF2RA gene/PMT therapy in a 22-year-old woman with hPAP caused by biallelic CSF2RA mutations (G174R, gene deletion). Methods Autologous, gene-corrected macrophages (cells) were prepared from bone marrow progenitors by transduction with a self-inactivating, 3rd generation lentiviral vector expressing a CSF2RA transgene, followed by ex vivo cell expansion, differentiation into macrophages, and cryopreservation until administration. The cell dose (11 million cells/kg ideal body weight) was based on mouse toxicology results and was equivalent in size to 16% of the adult human AM population. Cells were thawed, formulated in saline, tested, and instilled bronchoscopically into individual lung segments in two doses. The first was a split-dose delivered into 1, 4, then 14 segments sequentially at 2-month intervals. The second dose involved delivery into all 19 segments 16 months later. The rationale for this administration scheme was our focus on safety and because the achievable gene-correction rate had been 100% in mouse cells but only ∼50% in human cells. Results Two separate cell lots comprised 131% and 104% of the targeted production amount and met all lot-release criteria. Administration was nominal and not accompanied by bronchospasm, serious adverse events, or antibody responses to either the vector or transgene product. Evidence of biological efficacy included detection of vector DNA and transgene product in AMs, reduced bronchoalveolar lavage turbidity, and detection of morphologically normal AMs. Evidence of clinical efficacy included improvement in body mass index, DLCO%, exercise capacity, minor improvement in computed tomography, and reduction in surfactant burden (total pulmonary surfactant level) as demonstrated by time-dependent reduction in the ‘barrier signal’ from hyperpolarized 129Xe magnetic resonance imaging (MRI) (Figure). Conclusions Results show PMT therapy of hPAP was feasible, tolerable, safe, and efficacious. Clinical efficacy was proportional to cell dose and treatment duration and developed over 26 months of follow-up. Interestingly, hyperpolarized 129Xe MRI imaging was more sensitive in measuring surfactant burden than computed tomography. This abstract is funded by: NIH R33 HL156888
2025-09-27 | Pulmonary Alveolar Proteinosis: a 3-country cohort study Greece, Türkiye, Cyprus
Background: Pulmonary Alveolar Proteinosis (PAP) is a rare disease with inappropriate accumulation of surfactant in alveoli. Aim to characterize 3 cohorts in 3 Mediterranean neighbors (Greece, Türkiye, Cyprus) the last 20 years. Methods: Epidemiological, clinical and functional data were analyzed Results: Included are 124 patients: 32% Greece, 65% Türkiye, 3% Cyprus; 109 (88%) autoimmune PAP (aPAP), 13 (11%) secondary and 1 (1%) congenital; 49% male, 65% ever-smokers, followed-up 39 (16-83) months. At diagnosis median (IQR) age 39 (30-47) years, %-predicted FVC 77 (64-91), DLCO 55 (37-68),14% in LTOT. 7% had died. Whole lung lavage (WLL) in 51%, history of inhaled-GMCSF (sargramostim or molgramostim) in 44%. During FU, patients ameliorated [FVC% (p=0.007), DLCO% (p=0.001)]. Baseline characteristics of the three cohorts were similar. Significant differences were: WLL in Türkiye 64% vs 26% in Greece and Cyprus (p<0.001) and history of i-GMCSF as sole therapy 51% in Greece vs 9% in Türkiye (p<0.001). Deceased patients were more likely to be older (p=0.009), have secondary PAP (p<0.001), more comorbidities (p=0.035), higher oxygen-needs (p<0.001), worse functional status at FU (p=0.001) and complicated by pulmonary fibrosis (p<0.001). Patients who received i-GMCSF as sole therapy had no significant differences regarding age, disease severity or outcome compared to those with a history of WLL alone or in combination with i-GMCSF. Conclusion: In Türkiye WLL was the mainstay of treatment, while in Greece i-GM-CSF. Secondary PAP, age and pulmonary fibrosis negatively influenced prognosis. i-GMCSF as the sole therapy was not inferior to WLL or WLL followed by i-GMCSF irrespective of the severity of patients.
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