Regenerative Options for Knee Osteoarthritis

Cellular Medicine

Chris Evans PhD

REHABILATATION MEDICINE RESEARCH CENTER

DISCLOSURES

• Orthogen AG Supervisory Board• TissueGene Inc Scientific Advisory Board

(IP; licensing fee; honorarium)

• Aldabra LLC Co-Founder

Research funded by NIH, DoD, AO Foundation

OSTEOARTHRITIS HAS ALWAYS BEEN INCURABLE AND DIFFICULT TO TREAT

“Osteoarthritis is an easy disease to take care of. When the patient walks in the front door, I walk out the back door”.

Sir William Osler (1849 – 1919)

NormalJoint

OsteoarthriticJoint

PATHOLOGIES

Synovial thickening and inflammationChanges to bone

OsteophytesSub-chondral sclerosisCysts

Loss of articular cartilage

SYMPTOMS

PainLoss of Function

PATHOLOGY POTENTIAL

Synovitis High

Osseous Changes Potentially High

Cartilage Loss Very Difficult

POTENTIAL INTERVENTION IN MAJOR OA PATHOLGIES

Unlike many other tissues in the body, such as bone, articular cartilage has no intrinsic repair capacity.

WHY?

LOW MAG.

MEDIUM MAG.

HIGH MAG.

Articular cartilage has no intrinsic repair capacity because:

• Avascular• Aneural• Alymphatic• Complex architecture• No stem cells (?)

SEVERELY OSTEOARTHRITIC CARTILAGE

INTRA-ARTICULAR THERAPY

• Intuitively attractive for OA– No systemic sequelae– Limited number of affected joints– Higher local drug concentration– Reduced extra-articular side-effects– Reduced cost

• But more difficult than robbing banks*

*Evans CH: Drug delivery to chondrocytes Osteoarthritis Cartilage, 2015

HALF LIVES OF MOLECULES IN JOINTS

• Acridine orange (MW 370 Da) 0.23 h• NSAIDs and soluble steroids 1- 4 h• Anakinra (MW 17 kDa) ~ 4 h • Albumin (MW 67 kDa) 1.23 h• HA (MW 3x106 Da) 26.3 h

CELLULAR MEDICINE

• Do cells remain in joint after intra-articular injection?

• Do they provide therapeutic effect?

• Do they provide regenerative effect?

CANDIDATES FOR INTRA-ARTICULAR CELL THERAPY

• Synovial fibroblasts

• Chondrocytes

• Mesenchymal stem/stromal cells (MSCs)

WHAT IS A STEM CELL? STEM CELLS HAVE TWO IMPORTANT PROPERTIES:

1. They undergo assymetric cell division and thereby self-renew2. They give rise to other cell types

Mesenchymal Stem (Stromal) Cell

MSCs AS A SOURCE OF TROPHIC FACTORS

MSCs ARE ALSO IMMUNOSUPPRESSIVE

CAN THEY BE SUCCESSFULLY ALLOGRAFTED?

UNIVERSAL DONOR?

Visited 10/01/15

Allogeneic 6

Autologous10

Marrow MSCs 11

(BMC* 1)

Adipose MSCs 2

(SVF** 1)

Umbilical Cord MSCs 3

Phase I or I/II15

Phase II 3

* Bone marrow concentrate** Stromal vascular fraction

Commercialized in Veterinary Medicine

Recombinant Transforming

Growth Factor-b1

Pellet of marrow MSCs

Pellet of cartilage

IN VITRO CHONDROGENESIS

~ 1 month

Recombinant TGF-b1

AdenovirusTGF-b1

Pellet of marrow MSCs

Pellet of cartilage

IN VITRO CHONDROGENESIS BY GENE TRANSFER

~ 1 month

OA gene therapy protocol of TissueGene* Phase III trials in USA and Korea

Uses allograft chondrocytes expressing TGF-b

*CHE is on SAB

*CHE on SAB of TissueGene

*

ClinicalTrials.gov Identifier: NCT02072070

INVOSSA™

Current Surgical Repair Methods

• Mosaicplasty (OATS) (osteochondral plugs)

• Allograft (osteochondral plugs)

• Allograft (living cartilage fragments)

AUTO/ALLO-GRAFTING

CELL THERAPY•Autologous Chondrocyte Implantation (ACI)•Microfracture

BUT NOT IN OSTEOARTHRITIS

0

200

400

600

800

1000

1200

0 (-TGF)

0 0.1 1 10

IL-1 (ng/mL)

GA

G C

onte

nt (u

g/pe

llet)

0

100

200

300

400

500

0 (-TGF)

0 0.1 1 10

IL-1 (ng/mL)

GA

G p

er D

NA

(ng/

ng)

Interleukin-1 Inhibition of Chondrogenesis

Brackets:p<0.05 (n=4)

INTERLEUKIN-1 (IL-1)A Mediator of Pathology in OA

• Inflammatory • Promotes destruction of cartilage • Inhibits chondrogenesis• Alters bone turnover • Involved in pain

AAV.IL-1RaIL-1Ra

REGENERATION

CELLS

MORPHOGENS

MECHANICAL FACTORS

SCAFFOLDS

REGENERATIVE REHABILITATION

THANK YOU

REHABILATATION MEDICINE RESEARCH CENTER