Pirfenidone for the treatment of Hermansky–Pudlak syndrome pulmonary fibrosis
Introduction
Hermansky–Pudlak syndrome (HPS) consists of 8 genetically distinct subtypes, which share the common features of oculocutaneous albinism and a platelet storage pool deficiency [1], [2], [3], [4]. Approximately 15% of patients experience granulomatous colitis [2], [5], and people with HPS-1, HPS-2 and HPS-4 develop pulmonary fibrosis [6], [7], [8]. The cellular defect in HPS is abnormal biogenesis of lysosome-related organelles. Absence of dense bodies on platelet electron microscopy confirms the diagnosis of HPS [9]; the lack of these lysosome-related organelles causes the bleeding diathesis. In addition, defective melanosome formation in melanocytes results in hypopigmentation. The etiology of the granulomatous colitis and pulmonary fibrosis in HPS remains unknown.
Although rare worldwide, HPS is the most common recessively inherited form of albinism in Puerto Rico. HPS-1 is concentrated in the northwest section of Puerto Rico, where the frequency is 1 in 1800 [10] due to a founder mutation (i.e., a 16-bp duplication in exon 15 of HPS1) [11]. HPS-3 is primarily found in the center of the island due to a different founder mutation (i.e., a 3904-bp deletion in HPS3) [12].
Pulmonary fibrosis remains the most serious manifestation of HPS, and lung disease typically develops in the third to fifth decade of life [2], [7]. Patients present with progressive exertional dyspnea, fatigue, and chronic cough. Pulmonary function testing reveals a restrictive pattern with low diffusing capacity [6], [13] and hypoxemia with ambulation. High-resolution computed tomography (HRCT) scan imaging of the chest reveals ground-glass opacities, interstitial reticulations, and honeycombing [13]. The course of the lung disease varies among patients, but is universally progressive with an approximate two-year survival when forced vital capacity reaches 50% of predicted values [14]. There is no effective treatment except lung transplantation [15], which has been performed successfully in several patients.
The poor outcome associated with HPS pulmonary fibrosis prompted an initial clinical trial at the National Institutes of Health (NIH) Clinical Center using the anti-fibrotic agent, pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone). Pirfenidone, a small molecule that inhibits TGF-beta-mediated fibroblast proliferation and collagen synthesis in vitro, ameliorates cyclosporine- and bleomycin-induced pulmonary fibrosis in mice [16], [17]. The initial study demonstrated that pirfenidone was safe, and it showed modest benefit in treatment for HPS-1 pulmonary fibrosis with respect to the primary outcome parameter, rate of change in forced vital capacity [14]. This paper reports the results of a second study, which investigated pirfenidone in the treatment for mild to moderate HPS-1 and -4 pulmonary fibrosis.
Section snippets
Subjects and testing
Subjects were enrolled between 2005 and 2009 in protocol 97-HG-0085, which was approved by the National Human Genome Research Institute (NHGRI) Institutional Review Board. Primary inclusion criteria were a diagnosis of HPS-1 or − 4 confirmed by molecular analysis [3], [7], [8] and a forced vital capacity between 51 and 85% of predicted, regardless of radiographic evidence of fibrosis on HRCT. Subjects were excluded if they had exposures or other medical conditions associated with pulmonary
Baseline characteristics
Subjects in the placebo and pirfenidone groups were well matched for age, ethnicity, and severity of disease, as gaged by pulmonary function test results, 6-minute walk distance and partial pressure of oxygen, HRCT scores, and blood chemistries (Table 1). In particular, both groups showed similar degrees of impairment in forced vital capacity, total lung capacity, and diffusion capacity, indicating pulmonary restriction and mild reduction of gas exchange. A total of 35 subjects enrolled in the
Discussion
Of the 8 HPS subtypes, only types 1, 2 and 4 manifest pulmonary fibrosis [2]. HPS-1 and HPS-4 resemble each other clinically because the protein products of the HPS1 and HPS4 genes interact together as Biogenesis of Lyososome-related Organelles Complex-3, i.e., BLOC-3 [21]. This complex is considered to function in the early stages of intracellular vesicle formation and trafficking [3]. HPS-2 is due to defects in the beta-3A subunit of adaptor protein complex-3 [22], which functions in the
Disclosure statement
The authors have no conflict of interest regarding this work.
Acknowledgments
We would like to acknowledge the efforts of the Clinical Center pharmacists Judy Starling and George Grimes of the Pharmaceutical Development Service. We thank the members of the Hermansky–Pudlak syndrome network for their support, and most importantly, we thank our patients for their contributions to this research. This study was supported by the Intramural Research Programs of the National Human Genome Research Institute, the Eunice Kennedy Shriver National Institute of Child Health & Human
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2018, Molecular Genetics and MetabolismCitation Excerpt :In addition, reporting data from a historical placebo group is useful as a reference point, but it is not equivalent to comparison with a randomized control group. Indeed, the original clinical trials investigating pirfenidone as treatment for HPS pulmonary fibrosis compared subjects randomized to receive pirfenidone to those randomized to receive placebo [19, 20]. In conclusion, this retrospective analysis of three patients with HPS pulmonary fibrosis reveals that treatment with pirfenidone for several years may provide benefit with minimal side effects for some individuals with this fatal disease.
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