Patients With Intermittent Claudication Injected With ALDH Bright Cells

Peripheral Artery Disease (PAD) occurs when arteries in the arms and legs (most often the
legs) become narrowed by plaque. Because of this plaque, patients with PAD are also at
increased risk for heart attacks and strokes. Those with PAD often have intermittent
claudication (blockage of blood vessels in the leg). This blockage decreases blood flow to
the leg muscles, which can cause pain in one or both legs during exercise (such as during
walking). Intermittent means the pain comes and goes. Because PAD interferes with
circulation, worsening of this condition can increase pain in the leg; sometimes even during
periods of rest.

Bone marrow contains special stem cells that may promote blood vessel growth, prevent cell
death, and transform themselves into a number of tissues including new muscle. There is a
small subpopulation of bone marrow mononuclear cells, called aldehyde dehydrogenase-bright
(ALDHbr) cells, that is highly enriched in these types of stem cells. The enzyme in ALDHbr
cells responds to damage signals and may play an important role in tissue repair.

In this study we investigate the safety and efficacy of bone marrow derived stem cells with
particular characteristics in PAD patients with intermittent claudication and explore new
end-points to evaluate therapeutic effects using novel MRI imaging modalities as well as
traditional endpoints.

Inclusion Criteria:

1. Patients with atherosclerotic peripheral artery disease with classic claudication
(exercise-induced pain, cramps, fatigue, or other equivalent discomfort involving
large muscle groups of the leg(s) that is consistently relieved by rest) or atypical
leg pain (exertional leg pain that does not begin at rest or does not resolve
consistently with rest) as defined by the San Diego Claudication Questionnaire.

2. Age ≥40 years

3. Resting ankle-brachial index <0.90 or a resting toe-brachial index of <0.70 at
baseline testing

4. Presence of significant stenosis or occlusion of infrainguinal arteries including the
superficial femoral artery, popliteal artery and/or infrapopliteal arteries as
determined by: Duplex ultrasound imaging (occlusion or focal doubling of peak
systolic velocity of one or more affected segments) OR lower extremity computed
Tomography Angiography (CTA) OR lower extremity magnetic resonance angiography (MRA)
OR lower extremity catheter-based contrast arteriography. Each of these noninvasive
and invasive anatomic assessments will identify patients with at least a 50% stenosis
in the affected segment.

Exclusion Criteria:

1. Presence of any musculoskeletal disease, cardiac or pulmonary disease, or
neurological disease that limits the patient's ability to walk to fulfill protocol
requirements (claudication must be the consistent primary exercise limitation)

2. Inability to complete treadmill testing per protocol requirements.

3. Ability to walk for more than 12 minutes on the treadmill during treadmill testing.

4. Patients who identify both legs as equivocally symptomatic or alternate between
symptomatic legs on the baseline treadmill tests.

5. Patients with critical limb ischemia (ischemic rest pain or ischemia-related non
healing wounds or tissue loss (Rutherford categories 4-6).

6. Recent (<3 months) infrainguinal revascularization (surgery or endovascular
revascularization) or revascularization planned during study period

7. Patients with a patent infrainguinal bypass graft in the index limb, with or without
evidence of a hemodynamically significant stenosis or other defect (kinking,
pseudoaneurysm, or fistula). Patients with an occluded infrainguinal bypass graft or
a patent aortobifemoral or femoral-femoral bypass graft are NOT excluded.

8. Patients with >2+ lower extremity pitting edema

9. Patients with myelodysplastic syndrome (MDS)

10. Patients who are pregnant or lactating, planning to become pregnant in the next 12
months, or are unwilling to use acceptable forms of birth control during study
participation.

11. Congestive Heart Failure hospitalization within the last 1 month prior to enrollment

12. Acute coronary syndrome in the last 1 month prior to enrollment

13. Human Immunodeficiency Virus positive, active Hepatitis B Virus or Hepatitis C Virus
Disease

14. History of cancer within the last 5 years, except basal cell skin carcinoma

15. Any bleeding diathesis defined as an International Normalized Ratio ≥ 2.0 (off
anticoagulation therapy) or history of platelet count less than 100,000 or hemophilia

16. Contraindication to magnetic resonance imaging (MRI) (including knee/tibial/fibular
replacement hardware in the index leg) or known allergy to MRI contrast media

17. Chronic kidney disease [effective Glomerular Filtration Rate <30 by modification of
diet in renal disease (MDRD) or Mayo or Cockcroft-Gault formula]

18. Uncontrolled diabetes [Hemoglobin A1C (HbA1C)>8.5]

19. Planned change to (initiate or terminate) active involvement in a supervised exercise
program (e.g., with a trainer, exercise protocol, and goals, such as in a peripheral
arterial disease, cardiac or pulmonary rehabilitation program) during study
participation

20. Plans to change medical therapy during the duration of the study, (i.e. patients who
use cilostazol should remain on a stable dose for four weeks prior to enrollment and
should not change doses for the 6 months of the study duration.) As always,
cilostazol can be discontinued if new heart failure or intolerance occurs during
study participation.

21. Any condition requiring immunosuppressant medications (e.g., for treatment of organ
transplants, psoriasis, Crohn's disease, alopecia areata).

22. History of inflammatory or progressively fibrotic conditions (e.g. rheumatoid
arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary
fibrosis, retroperitoneal fibrosis).

23. Patients with any untreated stenosis > 70% of the distal aorta, common iliac, or
external iliac arteries by CT, Angiography or MRI imaging will be excluded from
enrollment (patients with previously successfully revascularized inflow stenoses may
enroll in PACE). Subjects who were screen failures for a flow-limiting proximal
lesion may be rescreened 3 months after successful angioplasty/stenting.

24. Inability to provide written informed consent due to cognitive or language barriers
(interpreter permitted)

25. Concurrent enrollment in another clinical interventional investigative trial.

26. Presence of any clinical condition that in the opinion of the principal Investigator
or the sponsor makes the patient not suitable to participate in the trial