Nebulization of Vitamin D for attenuation of lung inflammation Greg Wallace Bone Marrow transplant Jason C. Woods Pulmonary Medicine, Radiology, Physics

Problem Chronic Graft vs Host Disease of the lungs (Bronchiolitis Obliterans) Occurs after lung and bone marrow transplants Airway fibrosis Ineffective treatment options (high mortality, 22%) Late identification of the condition No early intervention strategy

Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disease (COPD) and is characterized by persistent airflow limitation caused by a combination of small airways disease, alveolar septum destruction and impaired secretions clearance. Chronic inflammation causes structural changes and narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory process, leads : To loss of alveolar attachments to the walls of the small airways. Reduction of the outward pulling and tethering of the walls of the small airways, which normally keeps them open. Sub-optimal tissue available to conduct gas exchange, leading to chronic difficulty in breathing It's caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke.

Main Causes for COPD Tobacco smoking Air pollution Genetics, congenital protein deficiency Chronic lung disease of childhood Occupational exposure

Common symptoms & complications Shortness of breath Caught, expectoration Dyspnea Fatigue and tightness in the chest Main Complications Wheezing or gasping for air Increased weight loss Swelling in the legs and feet Respiratory infections Heart problems Lung cancer High blood pressure in lung arteries Depression

COPD Pathophysiology Small airways are damaged, bronchiectasis, early collapse in expiration, failure to expectorate Extensive tissue damage, loss of elastic recoil lung hyperinflation Production of excessive secretions (goblet cell hyperplasia) and purulent sputum Lung damage is in homogenous COPD Healthy

Common Treatments Smoking cessation Anti- inflammatory Medications: Aerosolized drugs Bronchodilators Inhaled steroids Combination inhalers (bronchodilators and inhaled steroids) Oral medication Antibiotics Corticosteroids Physiotherapy/lung therapies (to improve mucus clearance and muscle strength): Oxygen therapy , Non-invasive ventilation, airway vibration Pulmonary rehabilitation program Surgery: Lung volume reduction surgery Lung tranplant Bullectomy

Therapeutic devices & Technologies LungFlute® Positive Expiratory Pressure Positive Expiratory Pressure and Oscillations Vibratory PEP Therapy System High Frequency Chest Wall Oscillation Inhalators Drug delivery device Positive Expiratory Pressure and Acoustic Oscillations

Disadvantages with the current devices and treatment COPD treatment is suboptimal (lancet 2017) Aerosolized therapy is paradoxically delivered better to the healthier areas and less to obstructed airways that need more medication Ineffective cough – ineffective expectoration – recurrent exacerbations Current devices do not give a complete solution (for lung therapy and effective drug delivery) Non personalized therapy and medication device based resulting non effective treatment and drug overdosing Small airways are not sufficiently been ventilated resulting: Ischemic changes and necrosis development Accumulation of mucus Inefficient medication treatment resulting recurrent hospital readmission

Our objective: administration of Vitamin D125 into the lungs 1-25 Vitamin D works wonders in skin GVHD Why not … in the lung? Chronic GVHD day 0 Chronic GVHD day 14

Problem No nebulized form of Vitamin D at present Vitamin D is lipid soluble No human studies in lung Surfactant, Vit A

Drug deposition in the “correct” airways Adolescent/adult lung Lower conducting airways (level 5-12) Subject in MRI Scanner Inhaled 129Xe Subject in MRI Scanner Maps of obstructed areas Thomen et al. J Cyst Fibros. 2016 Walkup et al. Pediatr Radiol. 2016

If we aerosolize vitamin D, need to determine What particle sizes will deliver maximal drug to level 5-12 airways? More challenging in pediatrics, since patients of all sizes (6-18 years old, 10-70 kg) 2. How well can we target individual airways and/or levels, based upon 129Xe MRI data? E.g., Level 5-12 airways? Apical segment, left lower lobe (bronchoscope)? Jason I changed the range from 15-10 kg, our patients usually are off the chart due to chronic illness

Need statement An affordable, portable, non-invasive inhalation/nebulizer device for effective aerosolized (Vitamin D125) drug delivery into the small airway on a daily basis treatment at patient home setting and hospital

Conclusions 1,25 Vitamin D would be used in asthma, COPD, ARDS, CF… Vitamin D 1,25 works very well in skin GVHD Key was 1,25 formulation Hyperpolarized gas MRI can depict & quantify lung GVHD early Very sensitive measure of early lung obstruction Can nebulize 1,25 form of Vitamin D Need to optimize delivery: CFD and particle size? Directed lavage? 1,25 Vitamin D would be used in asthma, COPD, ARDS, CF…

Molecular Medicine Reports 2017; 16:7432

Biology of Blood and Marrow transplantation 2017; epub before print