In vitro functional correction of Hermansky–Pudlak Syndrome type-1 by lentiviral-mediated gene transfer

Ikawa, Yasuhiro; Hess, Richard A.; Dorward, Heidi; Cullinane, Andrew R.; Huizing, Marjan; Gochuico, Bernadette R.; Gahl, William A.; Candotti, Fabio

doi:10.1016/j.ymgme.2014.11.006

Cited by 11 publications

(10 citation statements)

References 14 publications

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“…In type II alveolar epithelial cells of the lung, Rab38 helps maintain lamellar body morphology and surfactant homeostasis (24). The role of this defect in the development of pulmonary fibrosis is not known, but it is intriguing to note that abnormalities in surfactant proteins have been identified in idiopathic pulmonary fibrosis and related interstitial lung disorders (24,26,27). Disease mechanisms remain uncertain for the occurrence of granulomatous colitis, which has also been reported in approximately 15% of patients with HPS, not necessarily tracking with the occurrence of subtype risk for pulmonary fibrosis.…”

Section: Genetic and Functional Abnormalitiesmentioning

confidence: 99%

“…In fact, others have used lentiviruses for the transfer of the HPS1 gene into human dermal melanocytes in vitro and shown correction of the expression and function of the HPS1 gene in these cells (26). However, FOCUSED REVIEW difficulties in gene transfer methods in the lung, particularly to the alveolar epithelium, hamper progress in this area, and much still needs to be learned before gene therapy can be considered for potential correction of BLOC-3 dysfunction.…”

Section: Clinical Management Of Pulmonary Fibrosismentioning

confidence: 99%

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Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Section: Genetic and Functional Abnormalitiesmentioning

confidence: 99%

Section: Clinical Management Of Pulmonary Fibrosismentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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“…HPS pathogenesis and therapeutic options continue to be investigated, including through the use of organoids (Korogi et al, 2019; Strikoudis et al, 2019) and explorations of gene therapy (Ikawa et al, 2015; Iyer et al, 2019; Shen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

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“…In type II alveolar epithelial cells of the lung, Rab38 helps maintain lamellar body morphology and surfactant homeostasis [323]. The role of this defect in the development of pulmonary fibrosis is not known, but it is intriguing to note that abnormalities in surfactant proteins have been identified in idiopathic pulmonary fibrosis and related interstitial lung disorders [323,325,326]. Disease mechanisms remain uncertain for the occurrence of granulomatous colitis that has also been reported in approximately 15% of HPS patients, not necessarily tracking with occurrence of subtype risk for pulmonary fibrosis.…”

Section: Genetic and Functional Abnormalities In Hermansky-pudlak Synmentioning

confidence: 99%

“…In fact, others have used lentiviruses for the transfer of the HPS1 gene into human dermal melanocytes in vitro and shown correction of the expression and function of the HPS1 gene in these cells [325]. However, difficulties in gene transfer methods in the lung, particularly to the alveolar epithelium, hamper progress in this area, and much still needs to be learned before gene therapy is considered for potential correction of BLOC-3 dysfunction.…”

Section: Treatment and Management Of Hps-pfmentioning

confidence: 99%

The role of nicotine, a7 nicotinic acetylcholine receptors and extracellular matrix remodeling in pulmonary fibrosis.

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In vitro functional correction of Hermansky–Pudlak Syndrome type-1 by lentiviral-mediated gene transfer

Cited by 11 publications

References 14 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Hermansky–Pudlak syndrome: Mutation update

The role of nicotine, a7 nicotinic acetylcholine receptors and extracellular matrix remodeling in pulmonary fibrosis.

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