Mesenchymal Stem Cell Therapy for Lung Rejection

The overall clinical development strategy of this project is to conduct this Phase I dose
escalation study entitled "A pilot Study to Evaluate the Safety and Feasibility of
Mesenchymal Stem Cells to Induce Remission in Lung Transplant Patients Experiencing
Treatment-Refractory Moderate Lung Rejection". This study will be performed under this
current IND application and will be limited to the proposed 9 subjects (3 subjects in each
of dose escalating subject cohorts).

In this application we are proposing to evaluate safety and feasibility of allogeneic, bone
marrow (BM) derived mesenchymal stem cells (MSC) to induce remission of moderate treatment
refractory bronchiolitis obliterans (BO/BOS). Lung transplant patients with treatment
refractory BO/BOS (grade 3) who do not qualify for a second transplant have near 100%
mortality or extreme disability. MSCs are multi-potent cells that have the capacity to
induce tissue repair and modulate immune response. They have been used successfully in
preclinical and clinical studies to treat graft versus host disease (GVHD) and inflammatory
bowel disease. Patients that progressed to moderate BO despite adequate medical treatments
and who do not qualify for a second transplant will receive intravenous treatments of
allogeneic MSC. The safety measure will include tolerance of MSC infusion and absence of
significant cardiopulmonary compromise. The feasibility assessment will include ease of
recruitment, practical issue of transporting, preparing and infusing the MSCs.

The clinical assessment from this initial safety study is intended to demonstrate safety of
human MSC in subjects with BO and to evaluate the cell dose that demonstrates signs of
efficacy. Pending favorable safety results and pharmacokinetic and pharamcodynamic data
obtained in the current proposed study we will likely conduct additional human studies with
a more directed focus on the evaluation of efficacy while collecting additional safety
information.

Inclusion Criteria

1. Age range: 18 - 75 years

2. Gender: Male of female

3. Target disease or condition: Lung transplant recipients with treatment refractory
moderate BOS. Patient must have diagnosis of treatment refractory BO/BOS Subject must
have had, for each of the following three (3) treatment categories, either an
inadequate or lost response (recurrence or persistence of symptoms) to a drug in that
category within the past 24 months or documented intolerance to a drug in that
category at any time. Note that subject may currently be receiving steroids or
immunomodulators (see dosage requirements below) at the time of enrollment.

4. Enhanced steroid therapy

5. Enhanced immunosuppression

6. Trial/failure to other therapies like Azythromycin, anti-reflux therapy and others.

7. Informed consent form (ICF): Each patient will be required to sign an IRB approved
ICF. Only subjects who have signed the ICF will be enrolled into the study. The ICF
will include elements required by Mayo IRB and FDA in US 21CFR50.

8. Subject must have adequate renal function; calculated creatinine clearance of greater
than 30 ml/min.

9. Subject must be available for all specified assessments at the study site through the
completion of the study.

10. Subject must provide written ICF and authorization for use of and disclosure of PHI.

Exclusion Criteria

1. Patients with clinically significant illness with manifestations of significant organ
dysfunction which in the judgment of the PI or co-investigator would render the study
subject unlikely to tolerate the MSC infusion or complete the study

2. Evidence or history of malignancy

3. Evidence or history of autoimmune disorders independent of BO/BOS

4. Pregnant or breast-feeding

5. Positive screening for HIV Hepatitis B and Hepatitis C

6. Evidence of liver dysfunction; Liver profile showing alkaline phosphatase higher than
345 u/L, total bilirubin greater than 1.65 mg/dL, ALT greater than 275 units/L and
AST great than 240 units/L.

7. Evidence of significant cardiac dysfunction

8. Septicemia with high fever and hemodynamic instability

9. History of CMV pneumonitis

10. Patients who received any experimental therapy (drug or biologic) for any indication
within 3 months of the study enrollment