Autologous Stem/Stromal Cellular Stromal Vascular Fraction (cSVF) In Frailty-Aging Processes (GARM-W)

Use of Autologous Stem/Stromal Cellular Stromal Vascular Fraction (cSVF) In Cases Of Frailty and Aging Processes Using Autologous Stem-Stromal Cell Infusion in Patients With Aging Frailty And Wellness

With increasing age and health issues associated with aging, many systemic cellular and structural changes are known to occur. The intent of this trial is to determine the safety and efficacy of delivery of autologous cellular stromal vascular fraction (cSVF) to improve the quality of life and functional health. Isolation and concentration of cSVF will be documented. To acquire autologous cSVF, a 10+ teaspoon volume of subdermal adipose (fat) tissue and stroma is removed from the trunk or upper thigh area. Using a closed system with enzymatic digestion to isolate and concentrate these cells, is followed with returning these cSVF elements only via 500 cc Normal Saline delivered via peripheral vein (IV). Documentation of cellular numbers and flow cytometer viability testing is to be correlated with clinical outcomes as reported by patients and standardized Quality of Life (QoL) form tracking

With increasing age and health issues associated with aging, many systemic cellular and structural changes are known to occur. The intent of this trial is to determine the safety and efficacy of delivery of autologous cellular stromal vascular fraction (cSVF) to improve the quality of life and functional health. Isolation and concentration of cSVF will be documented. To acquire autologous cSVF, a 10+ teaspoon volume of subdermal adipose (fat) tissue and stroma is removed from the trunk or upper thigh area. Using a closed system with enzymatic digestion to isolate and concentrate these cells, is followed with returning these cSVF elements only via 500 cc Normal Saline delivered via peripheral vein (IV). Documentation of cellular numbers and flow cytometer viability testing is to be correlated with clinical outcomes as reported by patients and standardized Quality of Life (QoL) form tracking. Safety of use of certain allogeneic human mesenchymal stem cells (hMSC) has been tested and established along with the effectiveness of use. Autologous stem-stromal cells have been proven safe and effective in many applications and in clinical trials currently underway. These cells are easily obtained and isolated/concentrated in a closed system from patient's adipose derived stromal vascular fraction (cSVF). This is important as such tissues are uniquely the patient's cells, without the need for culture expansion of non-self human tissues, therefore potentially increasing availability to obtain non-allergenic, autologous cells known to be multipotent (can form a variety of specialized cell populations from the body) cell group within the cellular stromal vascular fraction (cSVF) present in essentially all tissues throughout the body (muscle, brain, bone, cartilage, nerve, skin, cardiac muscle, etc.). This study seeks to determine the safety, efficiency, and in subsequent studies (phase III type) to determine optimal dosages that are needed. Delivery of the cSVF will be returned to the patient's via a standard Normal Saline intravenous infusion (IV).

Closed microcannula harvesting of small volume of subdermal adipose tissue, including the stromal cellular and stromal tissue using sterile, disposable, microcannula system

Isolation and Concentration of cellular stromal vascular fraction (cSVF) using a Healeon Medical CentriCyte 1000 centrifuge, incubator and shaker plate with sterile Liberase enzyme (Roche Medical) per manufacturer protocols

cSVF from Arm 2 is suspended in a 500cc of sterile Normal Saline and deployed through 150 micron in-line filtration and intravenous route over 30-60 minute time frame.

Use of disposable, closed syringe microcannula harvest autologous adipose stroma and stem/stromal cells

Centricyte 1000, closed system digestion of stromal vascular fraction to isolate and concentrate stem/stromal cells associated with microvasculature

Sterile Normal Saline Suspension cSVF in 500 cc for Intravenous Delivery including 150 micron in-line filtration

Activity level Community Healthy Activities Model Program for Seniors (CHAMPS); Questionnaire; Self Reporting Assessment frequency and duration of various standing, walking, exercise tolerance, and changes in physical activity levels

4 meter gait speed test and short physical performance battery (SPPB); Score of <10 at baseline to predict ability to walk 400 meters

Multidimensional Fatigue Inventory Questionnaire (MFI); 20 Item self-reporting general fatigue, mental fatigue, reduced motivation, reduced activity levels

Short Mobility Performance Battery (SPPB) Assessment; Evaluates lower extremity function via standing balance (time), 4 meter gait speed and 5 repetition sit to stand (ability)

Inclusion Criteria: Be >40 and <90 years of age and willing and able to provide written informed consent Those aging and frail patients who have noted compromise to activities or work requirements due to increasing age Ability to execute a 6 minute walk test distance of >200 meters and <1000 meters Loss of energy and exercise tolerance over 6 month period minimum Current clinical history of malignancy within 3 years, except for curable skin lesions including basal cell carcinoma, or squamous cell carcinoma Must have the ability to provide Informed Consent Exclusion Criteria: Medical conditions which prevent the ability of assessment of walk distance testing criteria Have disabling neurodegenerative disorder which would impede interpretation of outcomes Have a score of <24 on the Mini Mental State Examination (MMSE) History of malignancy within 2 years (excluding curative skin lesion of basal cell carcinoma, melanoma-in-situ, or cervical carcinoma Have clinically important abnormal screening laboratory values, including, but not limited to: Hemoglobin <10 g/dL; White blood cell count (WBC) <2500/mL; Platelet count microliters <100000/uL(microliters); Genetic Coagulopathy history Uncontrollable hypertension Systemic disorders that preclude completion of the testing or out of medical management control in the opinion of the PIs or Primary Care Provider Expected lifespan of less that 6 months Current drug abuse history < 6 months Alcohol abuse within 6 months of enrollment Serious or life threatening co-morbidities that in the opinion of investigators, may compromise the safety or compliance with the study guidelines and tracking.

Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA, Ershler WB, Harris T, Fried LP. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006 Jun;54(6):991-1001. doi: 10.1111/j.1532-5415.2006.00745.x.

Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013 Mar 2;381(9868):752-62. doi: 10.1016/S0140-6736(12)62167-9. Epub 2013 Feb 8. Erratum In: Lancet. 2013 Oct 19;382(9901):1328.

Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc. 2010 Apr;58(4):681-7. doi: 10.1111/j.1532-5415.2010.02764.x. Epub 2010 Mar 22.

Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217. doi: 10.1016/j.cell.2013.05.039.

Rockwood K, Mitnitski A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med. 2011 Feb;27(1):17-26. doi: 10.1016/j.cger.2010.08.008.

Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med. 2011 Feb;27(1):1-15. doi: 10.1016/j.cger.2010.08.009.

Tompkins BA, DiFede DL, Khan A, Landin AM, Schulman IH, Pujol MV, Heldman AW, Miki R, Goldschmidt-Clermont PJ, Goldstein BJ, Mushtaq M, Levis-Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro-Casiano M, Da Fonseca M, Golpanian S, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El-Khorazaty J, Mendizabal A, Green G, Oliva AA, Hare JM. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1513-1522. doi: 10.1093/gerona/glx137.

Peffers MJ, Collins J, Loughlin J, Proctor C, Clegg PD. A proteomic analysis of chondrogenic, osteogenic and tenogenic constructs from ageing mesenchymal stem cells. Stem Cell Res Ther. 2016 Sep 14;7(1):133. doi: 10.1186/s13287-016-0384-2.

Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006 Feb;5(1):91-116. doi: 10.1016/j.arr.2005.10.001. Epub 2005 Nov 28.

Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 2008 Mar;129(3):163-73. doi: 10.1016/j.mad.2007.12.002. Epub 2007 Dec 17.

Golpanian S, DiFede DL, Khan A, Schulman IH, Landin AM, Tompkins BA, Heldman AW, Miki R, Goldstein BJ, Mushtaq M, Levis-Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro-Casiano M, Pujol MV, Da Fonseca M, Oliva AA Jr, Green G, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El-Khorazaty J, Mendizabal A, Goldschmidt-Clermont PJ, Hare JM. Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1505-1512. doi: 10.1093/gerona/glx056.

Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86. doi: 10.1016/j.jacc.2009.06.055.

Hare JM, DiFede DL, Rieger AC, Florea V, Landin AM, El-Khorazaty J, Khan A, Mushtaq M, Lowery MH, Byrnes JJ, Hendel RC, Cohen MG, Alfonso CE, Valasaki K, Pujol MV, Golpanian S, Ghersin E, Fishman JE, Pattany P, Gomes SA, Delgado C, Miki R, Abuzeid F, Vidro-Casiano M, Premer C, Medina A, Porras V, Hatzistergos KE, Anderson E, Mendizabal A, Mitrani R, Heldman AW. Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial. J Am Coll Cardiol. 2017 Feb 7;69(5):526-537. doi: 10.1016/j.jacc.2016.11.009. Epub 2016 Nov 14.

Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013 Jun;143(6):1590-1598. doi: 10.1378/chest.12-2094.

Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015 Apr 10;116(8):1413-30. doi: 10.1161/CIRCRESAHA.116.303614.

Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, Mitnitski A. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005 Aug 30;173(5):489-95. doi: 10.1503/cmaj.050051.

Golpanian S, DiFede DL, Pujol MV, Lowery MH, Levis-Dusseau S, Goldstein BJ, Schulman IH, Longsomboon B, Wolf A, Khan A, Heldman AW, Goldschmidt-Clermont PJ, Hare JM. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget. 2016 Mar 15;7(11):11899-912. doi: 10.18632/oncotarget.7727.

McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol. 2009 Aug;21(4):418-24. doi: 10.1016/j.coi.2009.05.023. Epub 2009 Jun 29.

Kawamoto A, Katayama M, Handa N, Kinoshita M, Takano H, Horii M, Sadamoto K, Yokoyama A, Yamanaka T, Onodera R, Kuroda A, Baba R, Kaneko Y, Tsukie T, Kurimoto Y, Okada Y, Kihara Y, Morioka S, Fukushima M, Asahara T. Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells. 2009 Nov;27(11):2857-64. doi: 10.1002/stem.207.

Golpanian S, Schulman IH, Ebert RF, Heldman AW, DiFede DL, Yang PC, Wu JC, Bolli R, Perin EC, Moye L, Simari RD, Wolf A, Hare JM; Cardiovascular Cell Therapy Research Network. Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease. Stem Cells Transl Med. 2016 Feb;5(2):186-91. doi: 10.5966/sctm.2015-0101. Epub 2015 Dec 18.

Schuleri KH, Feigenbaum GS, Centola M, Weiss ES, Zimmet JM, Turney J, Kellner J, Zviman MM, Hatzistergos KE, Detrick B, Conte JV, McNiece I, Steenbergen C, Lardo AC, Hare JM. Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J. 2009 Nov;30(22):2722-32. doi: 10.1093/eurheartj/ehp265. Epub 2009 Jul 8.

Siddiqi S, Sussman MA. Cell and gene therapy for severe heart failure patients: the time and place for Pim-1 kinase. Expert Rev Cardiovasc Ther. 2013 Aug;11(8):949-57. doi: 10.1586/14779072.2013.814830.

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available. Erratum In: Am J Respir Crit Care Med. 2016 May 15;193(10):1185.

Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R, Arnold A, Newman AB; Cardiovascular Health Study. The 6-min walk test: a quick measure of functional status in elderly adults. Chest. 2003 Feb;123(2):387-98. doi: 10.1378/chest.123.2.387.

Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. CHAMPS physical activity questionnaire for older adults: outcomes for interventions. Med Sci Sports Exerc. 2001 Jul;33(7):1126-41. doi: 10.1097/00005768-200107000-00010.

Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue. Physiol Rev. 2016 Jul;96(3):1127-68. doi: 10.1152/physrev.00019.2015.

Rando TA, Wyss-Coray T. Stem cells as vehicles for youthful regeneration of aged tissues. J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1(Suppl 1):S39-42. doi: 10.1093/gerona/glu043.

Raggi C, Berardi AC. Mesenchymal stem cells, aging and regenerative medicine. Muscles Ligaments Tendons J. 2012 Oct 16;2(3):239-42. Print 2012 Jul.

Tetta C, Consiglio AL, Bruno S, Tetta E, Gatti E, Dobreva M, Cremonesi F, Camussi G. The role of microvesicles derived from mesenchymal stem cells in tissue regeneration; a dream for tendon repair? Muscles Ligaments Tendons J. 2012 Oct 16;2(3):212-21. Print 2012 Jul.

Alexander, R. Understanding Adipose-derived Stromal Vascular Fraction (AD-SVF) Cell Biology and Use on the Basis of Cellular, Chemical, Structural and Paracrine Components: A Concise Review. J Prolotherapy, 2012 J of Prolo (JOP) 4:e13777

Alexander, R., Understanding Mechanical Emulsification (Nanofat) Versus Enzymatic Isolation of Tissue Stromal Vascular Fraction (tSVF) Cells from Adipose Tissue: Potential Uses in Biocellular Regenerative Medicine Understanding J prolo 2016

ALEXANDER, ROBERT W., "Biocellular Regenerative Medicine: Adipose-Derived Stem/Stromal Cells & Matrix" . World Biomedical Frontiers, Section of Stem Cells, 2017 July. http://biomedfrontiers.org/stem-cells-2017-7-1.

ALEXANDER, ROBERT W., "Use of Microcannula Close Syringe System For Safe And Effective Lipoaspiration and Small Volume Autologous Fat Grafting", Am J Cosm Surg 2013, 30(2): 1-12