Autologous Culture Expanded Mesenchymal Stromal Cells for Knee Osteoarthritis

Interventions to alter the natural course of osteoarthritis (OA) in the knee are elusive and
joint replacement remains the definitive management for refractory, end-stage disease. The
Mayo Clinic has a large, ongoing experience using autologous adipose derived mesenchymal
stromal cells (AMSCs) for the treatment of a variety of other diseases under INDs. Thus far,
the treatments have been well tolerated. These data along with the investigators'
pre-clinical animal studies and published experiences using related approaches lead the
investigators to believe that this approach provides a reasonable safety profile to treat
patients with refractory painful knee OA. The purpose of the current study is to investigate
the safety and feasibility of single and multiple injections of autologous, culture expanded
AMSCs in subjects with painful, refractory knee OA. Subjects with unilaterally symptomatic
mild to severe knee OA will be enrolled based on satisfaction of inclusion and exclusion
criteria.

Inclusion Criteria:

1. Male or female ages 40-70 years

- Females of childbearing potential must have a negative pregnancy test prior to
receiving the study drug and will agree use adequate contraception (hormonal or
barrier method or abstinence) from the time of screening to a period of 1 year
following completion of the drug treatment cycle. Females of childbearing
potential are defined as premenopausal and not surgically sterilized, or
post-menopausal for fewer than 2 years. A urine pregnancy test will be performed
prior to the administration of the study drug to confirm negative results. If the
urine pregnancy test is positive, the study drug will not be administered and the
result will be confirmed by a serum pregnancy test. Serum pregnancy tests will be
performed at a central clinical laboratory, whereas urine pregnancy tests will be
performed by qualified personnel using kit

- Females becoming pregnant during the study will continue to be monitored for the
duration of the study or completion of the pregnancy, whichever is longer.
Monitoring will include perinatal and neonatal outcome. Any SAEs associated with
pregnancy will be recorded. Females in the multiple-dose cohorts (M50 and M100)
who become pregnant during the treatment cycle will not receive their remaining
injections.

2. Chronic (> 3 months), unilaterally symptomatic, primary femorotibial knee OA

3. Radiographic medial and/or lateral femorotibial knee OA at least Kellgren-Lawrence
grade 2 accompanied by definite joint space narrowing as agreed upon by two study
co-investigators

4. Previous 6 week or longer trial of one of the following conservative treatments:
activity modification, weight loss, physical therapy, anti-inflammatory medications or
injection therapy (e.g. cortisone, hyaluronic acid/viscosupplement)

5. Able to routinely walk without assistance (e.g. cane, walker)

6. Clinically stable target knee

7. No surgery planned in the target knee for at least 12 months following the last
injection

8. Completed general physical evaluation with primary care provider within 12 months of
enrollment

9. Fully understanding of the requirements of the study and willingness to comply with
the treatment plan, including fat harvesting, laboratory tests, diagnostic imaging,
repeated knee injections/aspirations, arthroscopic examination and follow-up visits
and assessments

10. Can provide written informed consent and complete HIPAA documentation after the nature
of the study is fully explained and prior to any study-related procedure

Exclusion Criteria:

1. Pregnant or nursing, or planning on becoming pregnant during the study period

2. Congenital or acquired malformation of the target knee resulting in significant
deformity or leading to problems with the study treatment or analysis of the results

3. Significant malalignment on full length, standing radiographs

4. Orthopedic hardware or implantable devices anywhere in the body, other than dental

5. Surgery on the index knee within 1 year of study enrollment

6. Injections of any into the index knee within 3 months prior to study enrollment

7. Locking, catching, give-away or another major mechanical symptoms of the target knee

8. Symptomatic patellofemoral arthritis or chondromalacia in the index knee

9. History of intra-articular infection in the index knee

10. History of superficial infection in the index knee within 6 months of study
enrollment, or evidence of current superficial infection affecting the index knee

11. History of falls requiring medical attention, or gait instability

12. Abnormal hematology (complete blood count with differential), blood chemistry, or
urinalysis screening laboratory results, including aspartate aminotransferase (AST),
alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine, and
CRP

13. Body mass index (BMI) > 40 kg/m2

14. Taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix)

15. Taking herbal therapies or supplements within 4 weeks of enrollment or unwilling to
avoid use of herbal therapies or supplements until at least 30 days following
completion of the study drug treatment cycle (includes, but not limited to chondroitin
sulfate, diacerein, n-glucosamine, piascledine, and capsaicin)

16. Taking non-steroidal anti-inflammatory medications (e.g. COX-2 inhibitors) without a
stable dosing regimen for at least 4 weeks before baseline evaluation, or anticipating
not remaining on a stable dose until at least 30 days following completion of the
study drug treatment cycle

17. Use of electrotherapy or acupuncture for OA, unless there is a stable regimen for at
least 4 weeks before baseline assessment

18. Taking anti-rheumatic disease medication (including methotrexate or other
antimetabolites) within 3 months prior to study enrollment

19. On chronic, immunosuppressive transplant therapy or having a chronic,
immunosuppressive state, including use of systemic steroids/corticosteroids

20. Current tobacco product use, including nicotine patch or other nicotine products

21. Systemic inflammatory, rheumatological or connective tissue disorder including but not
limited to rheumatoid arthritis, systemic sclerosis, system lupus erythematosus, and
Ehlers-Danlos Syndrome

22. Rheumatological or inflammatory disease of the knee or chondrocalcinosis/calcium
pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of
the knee associated with juxta-articular Paget's disease of the femur or tibia,
ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint,
villonodular synovitis, and synovial chondromatosis

23. Ongoing infectious disease, including but not limited to tuberculosis, HIV, hepatitis,
and syphilis

24. Clinically significant cardiovascular (e.g. history of myocardial infarction,
congestive heart failure or uncontrolled hypertension > 90 mmHg diastolic and/or 180
mmHg systolic), neurologic (e.g. stroke, TIA) renal, hepatic, orthopedic (e.g. surgery
on other weight bearing joints that will interfere with study, osteoporosis, acute
lower body fractures), or endocrine disease (e.g. diabetes).

25. Vascular or neurological disorder affecting the index either lower limb

26. History of cancer/malignancy with the exception of adequately treated basal cell or
squamous cell carcinoma of the skin not associated with the target knee

27. History of blood dyscrasia, including but not limited to anemia, thrombocytopenia, and
monoclonal gammopathy

28. Participation in a study of an experimental drug or medical device within 3 months of
study enrollment

29. Known allergy to local anesthetics of other components of the study drug

30. Any contraindication to MRI scan according to MRI guidelines, or unwillingness to
undergo MRI procedures

31. History of or current evidence of alcohol or drug abuse or dependence, recreational
use of illicit drug or prescription medications, or have use of medical marijuana
within 30 days of study entry

32. Any illness or condition which, in the investigators' judgement will interfere with
the patient's ability to comply with the protocol, compromise patient safety, or
interfere with the interpretation of the study results