Novel Treatment for Hermansky-Pudlak Syndrome Pulmonary Fibrosis

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder that can result in a wide range of symptoms, depending upon which genetic mutation a patient inherits. In three of the 10 forms of HPS, patients develop pulmonary fibrosis (PF), in which tissues deep in the lungs become scarred, interfering with the ability to breathe. PF is a leading cause of premature death in adults with HPS, and there are no treatments approved by the Food and Drug Administration (FDA) for HPS-PF. Scientists from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Human Genome Research Institute (NHGRI) jointly identified that increased activity of two biological pathways contributes to the development of lung fibrosis in HPS-PF. The lead collaborators discovered that these two pathways can be blocked by a single drug molecule, offering protection against lung fibrosis in animal models of HPS. This project will further develop this drug candidate for clinical testing in patients.

Scientific Synopsis

Hermansky-Pudlak syndrome is a rare genetic disorder primarily of lysosome-related organelle biogenesis. There are 10 different types of HPS, depending on which genetic mutation is inherited. Patients with HPS-1, HPS-2 or HPS-4 develop pulmonary fibrosis. In the absence of a Food and Drug Administration (FDA)-approved therapy for HPS-PF, there is an urgent need to identify new therapeutic targets and treatment strategies.

It has been shown that the cannabinoid-1 receptor (CB1R) is overactivated in fibrotic lung tissue of mice and humans with HPS. In previous studies, rimonabant, a CB1R antagonist, demonstrated a modest ability to mitigate fibrosis in animal models. However, the neuropsychiatric side effects of CB1R inhibitors, through the blockade of receptors expressed in the central nervous system (CNS), led to rimonabant being withdrawn from all clinical use. In addition to CB1R, the activity of inducible nitric oxide synthase (iNOS) is also increased in PF, promoting lung inflammation and progression of fibrosis. Because the pathogenesis of HPS-PF is complex, targeting multiple pathways has been recommended as an approach to improve therapeutic efficacy.

To target these independent drivers of PF simultaneously in HPS, the novel drug candidate MRI-1867 was designed as a dual inhibitor of both CB1R and iNOS. To avoid the CNS side effects of the first-generation CB1R antagonists, MRI-1867 was designed to be restricted to the peripheral tissues and specifically excluded from the brain. MRI-1867 is orally bioavailable, and in chronic treatment in animal models of PF it provided increased antifibrotic efficacy compared with targeting either CB1R or iNOS alone.

Lead Collaborator

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD
Resat Cinar, Pharm., Ph.D.
George Kunos, M.D., Ph.D.
Malliga R. Iyer, Ph.D.

Public Health Impact

Pulmonary fibrosis is a progressive condition. Symptoms worsen over time and can range from breathing problems, such as shortness of breath even while at rest, to more severe symptoms, such as lung infections, blood clots, pulmonary hypertension and heart failure. PF is a leading cause of premature death in HPS patients, and there are no FDA-approved treatments for HPS-PF.


The TRND project team has developed a comprehensive project plan to advance MRI-1867 toward clinical testing. TRND scientists are developing a synthetic process and a suitable formulation for manufacturing MRI-1867; developing and validating the analytical and bioanalytical assays necessary to evaluate the drug product; and conducting preclinical pharmacokinetics, safety and toxicology studies that will enable the collaborators to submit an Investigational New Drug application with the Food and Drug Administration to initiate a Phase I clinical trial.