Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis Autoimmune Pulmonary Alveolar Proteinosis
Condition: Autoimmune Pulmonary Alveolar Proteinosis
MeSH terms: Pulmonary Alveolar Proteinosis; Autoimmune Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      Pulmonary alveolar proteinosis (PAP) is a syndrome of surfactant accumulation, respiratory
      failure, and innate immune deficiency for which therapy remains limited to whole lung lavage
      (WLL), an invasive physical procedure to remove surfactant unavailable at most medical
      centers. While PAP occurs in multiple diseases affecting men, women, and children of all ages
      and ethnic origins, in 85% of patients, it occurs as an idiopathic disease associated with
      neutralizing GM-CSF autoantibodies. Basic science and translational research has shown that
      idiopathic PAP is an autoimmune disease in which disruption of GM-CSF signaling impairs the
      ability of alveolar macrophages to clear surfactant and perform host defense functions.

      Recently, it has been shown that cholesterol toxicity drives pathogenesis in alveolar
      macrophages from GM-CSF deficient (Csf2-/-) mice and patients with autoimmune PAP. Loss of
      GM-CSF signaling reduces PU.1/CEBP-mediated expression of PPARγ and its downstream target
      ABCG1 (a cholesterol exporter important in macrophages). The cell responds by esterifying and
      storing cholesterol in vesicles to reduce toxicity. Eventually, vesicles fill the cell,
      impair intracellular transport and reduce uptake and clearance of surfactant from the lung
      surface resulting in disease manifestations. Recent data indicates that pioglitazone, a PPARγ
      agonist currently approved by the FDA for human use, increases cholesterol/surfactant
      clearance by alveolar macrophages from autoimmune PAP patients and Csf2-/- mice. Importantly,
      pioglitazone significantly reduced the severity of PAP lung disease in Csf2-/- mice after
      several months of therapy. Together, these observations suggest pioglitazone could be
      'repurposed' as pharmacologic therapy for PAP.
    

Detailed description: 
      PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure
      that occurs in multiple diseases that can be classified on the basis of pathogenesis into
      three groups: primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP,
      hereditary PAP), secondary PAP (caused by reduction in alveolar macrophage numbers and/or
      functions), and metabolic disorders of surfactant production-related PAP (caused by mutations
      in genes required for normal surfactant production). Blood tests are capable of identifying
      the PAP-causing disease in about 95% of patients.

      Research has demonstrated that aPAP is caused by a high level of GM-CSF autoantibodies, which
      block GM-CSF signaling. Normally, alveolar macrophages clear (remove) about half of the used
      surfactant from air sacs (alveoli) in the lungs. Without GM-CSF, alveolar macrophages have a
      reduced ability to clear surfactant, which builds up in the alveoli and the blocks delivery
      of oxygen into the blood, resulting in a low blood oxygen level and a reduced oxygen delivery
      to tissues of the body. This macrophage defect is thought to occur because loss of GM-CSF
      stimulation causes reduced activity of PPAR-gamma, a molecule present within alveolar
      macrophages that they require to simulate the ability to clear surfactant: the reduction in
      PPAR-gamma activity cause a functional impairment of surfactant clearance by alveolar
      macrophages.

      Currently, no pharmacologic agent has been FDA-approved as therapy aPAP: it is currently
      treated by whole lung lavage, a procedure requiring general anesthesia and a breathing
      machine the lungs are individually filled with saline and drained repeatedly to physically
      remove the excess surfactant. Recent research has shown that pioglitazone, a drug that
      activates PPAR-gamma, is able to increase the ability of cultured macrophages to clear
      surfactant in the laboratory and that oral administration is able to reduce lung disease
      severity and be well-tolerated in a mouse model of aPAP. Currently, pioglitazone is approved
      by the FDA for treatment of increased blood sugar in patients with diabetes.

      This study is a pilot phase I/II human clinical trial of oral pioglitazone as therapy for
      autoimmune PAP. The target population is adults with aPAP who have measurable, clinically
      significant disease satisfying all of the inclusion and exclusion criteria. The study design
      will involve recruitment, screening, and enrollment of participants into a phase I,
      open-label, dose-escalating, single site study. Oral pioglitazone will be administered to
      autoimmune PAP patients with a personalized dose escalation plan beginning at 15 mg per day,
      advancing to 30 mg per day and then 45 mg per day, if tolerated, in 12 week increments.
      Adverse events (AEs), serious AEs (SAEs), and pharmacodynamics (PD) parameters will be
      evaluated. The experimental approach will evaluate 1) safety of oral pioglitazone by
      documenting occurrence of treatment-emergent AEs and SAEs, 2) physiological effects of oral
      pioglitazone by measuring changes in the physiological, clinical, and quality of life
      parameters and 3) biochemical effects of pioglitazone on the transcriptome, phenotype, and
      function of mononuclear phagocytes (alveolar macrophages and monocytes) from autoimmune PAP
      patients. Anticipated results will determine the safety, efficacy, and biochemical effects of
      oral pioglitazone in patients with autoimmune PAP. These results will impact the field by 1)
      monitoring safety of oral pioglitazone in autoimmune PAP patients, 2) translating existing
      preclinical data in humans, and 3) demonstrating the results of pioglitazone in a
      personalized treatment plan with dose escalation in a pilot trial to evaluate the efficacy of
      oral pioglitazone for aPAP.
    

Intervention name(s): Pioglitazone
Intervention type(s): Drug
Intervention description(s): Participants will receive three doses of Pioglitazone, 15 mg/day for 12 weeks, 30 mg/day for 12 weeks, and 45 mg/day for 12 weeks
Other intervention name(s): Actos
Intervention MeSH terms: Pioglitazone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science