Stem Cell Strategies for the Treatment of Chronic Asthma

Asthma is a significant global health challenge with the prevalence of allergic asthma increasing by 1% each year. Atopic asthma is a complex disorder driven by cellular mechanisms in response to allergens. The response is two-fold; a chronic inflammatory response accompanied by remodelling of the respiratory airways. Airway remodelling is characterised by smooth muscle hypertrophy (and mucous gland) and hyperplasia, fibrosis of the sub-epithelium and reticular basement thickening, and epithelial damage. Over time the airway suffers remodelling due to thickening of the smooth muscle component which is in turn accompanied by irreversible fibrotic changes and a tendency towards treatment unresponsiveness. The inflammatory response on the other hand is characterised by IgE activation of mucous mast cells, infiltration of eosinophils, increased CD4+Th2 lymphocytes, and Type 2 cytokine secretion (e.g. IL13). The primary challenge in the development of new asthma treatments is to deliver long-lasting relief to the inflammatory response and also to 'repair' the remodelling associated with repeated asthmatic events. Mesenchymal stem cells (MSC), derived primarily from the bone marrow, have a multipotent differentiation potential (primarily bone, fat, and cartilage) and are currently in clinical trial for over 350 diseases and disorders. These include diverse areas such as ischemic stroke, graft vs. host disease, Crohns disease, and type 1 diabetes alongside anticipated applications related to the musculoskeletal system. Their application into the treatment of musculoskeletal damage relies primarily on functional incorporation (differentiation into the damaged tissue to repair in situ). In contrast their application in many other instances is due to their unique inherent characteristic, namely their immunomodulatory role. MSC secrete a wide range of growth factors and cytokines (the secretome) which have the capacity to silence immune reactions preventing T cell activation. In addition to this property the MSC secretome has also been shown to reverse the remodelling associated with fibrotic disease.

Inclusion criteria

Men or women, age (18-70 years old), II. Lifelong never-smokers or ex-smokers (< 10 pack years). (1 pack year= 20 cigarettes/day for 1 year).

III. Must be competent to give written informed consent. IV. Female participants of child bearing potential must have a negative urine pregnancy test prior to bronchoscopy.

V Potential participants must meet the safety criteria to have a Spirometry test where necessary.

vi Must meet the safety criteria to have a bronchoscopy.

Asthmatic participants:

VI. Have a physician diagnosis of asthma. VII. All asthma patients will have either bronchodilator reversibility of ≥12% or 200 mL at screening, or historic data confirming bronchodilator reversibility or bronchial hyperreactivity to methacholine (PC20). Those without prior confirmed reversibility will have bronchodilator reversibility testing to salbutamol at screening and the asthma control questionnaire (ACQ) administered. Where reversibility to salbutamol is inconclusive a methacholine challenge will be performed.

VIII. Must have stable disease with no recent flare-ups (within 4 weeks). IX. Oxygen saturations whilst breathing room air must be > 90% (a measure of how well the lungs are providing oxygen to the body).

X. When blowing forcefully into a tube (forced expiratory volume or FEV), the patient must be able to blow out at least one litre of air in the first second (FEV1 > 1Litre).

Non-asthmatic participants:

XI. Have no physician diagnosis of asthma. XII. Have no evidence of any long term lung condition or any other disabling condition and they must not have had a chest infection in the preceding 4 weeks.

Exclusion criteria

I. Significant smoking history (>10 pack year). II. Significant lung co-morbidities III. Patient unable to give informed consent IV. History of myocardial infarction within the preceding 6 weeks V. Any subject with asthma who requires home oxygen will not be included for safety reasons