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Future Directions. Steven Abramson M.D. NYU Langone Medical Center. Future Directions: 3-10 Year Horizon. Improved analgesics Structure modification (DMOADs) Clinical and pathogenic phenotyping Imaging and biochemical markers Genetic susceptibility for incident and progressive disease

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Future directions

Future Directions

Steven Abramson M.D.

NYU Langone Medical Center


Future directions 3 10 year horizon
Future Directions: 3-10 Year Horizon

Improved analgesics

Structure modification (DMOADs)

Clinical and pathogenic phenotyping

Imaging and biochemical markers

Genetic susceptibility for incident and progressive disease

Minimally invasive surgical advances

Tissue repair


Future 1 biomarkers focus on detecting and treating early molecular stages of osteoarthritis
Future 1: Biomarkers: Focus on Detecting and Treating Early Molecular Stages of Osteoarthritis

Biomarker

Endpoints

Defining Structural Outcomes

X-RAY

MRI

Ultrasound

Bone Scintigraphy

BIOMARKERS

Pain

MOLECULAR

PRERADIOGRAPHIC

RADIOGRAPHIC

JOINT REPLACEMENT

Prevention

Defining Disease State

Devices

(Courtesy of V. Kraus)


A Molecular Stages of Osteoarthritis

B

100 ms

0

Proteoglycan Loss in Early Osteoarthritis

T1=68±4ms

(R. Regatte, NYUHJD, unpublished data)


Oa is condition of heterogeneous etiologies

OA is condition of Molecular Stages of Osteoarthritisheterogeneous etiologies

…which develops over decades

Future 2: OA Phenotypes


Oa phenotype understanding early molecular mechanisms
OA “Phenotype”: Understanding Early Molecular Mechanisms Molecular Stages of Osteoarthritis

Aging processes

Genetic susceptibility

Mechano-transduction

Cartilage Biology

Bone biology

Synovial events

Metabolic events


Oa phenotype disease mechanisms
OA Phenotype & Disease Mechanisms Molecular Stages of Osteoarthritis

Primary

Post-traumatic

Metabolic

Age related

CCPD

Kashin-Beck Disease (?)

Estrogen

Genetics

Biomechanics

Catabolic State

OA

Rx

Progression


Importance of oa phenotypes in early osteoarthritis

Importance of OA Phenotypes Molecular Stages of Osteoarthritisin Early Osteoarthritis

Mitochondria, AGE, Aspartate, SirT1

Aging

ADAMTS, MMP-13, DDR2, NO

Cartilage

BMP, VEGF, RANKL, Wnt, TGFb

Bone

IL-1, IL-1RN, COX-2, TNFa

Inflammation

Adipokines, estrogen, oxLDL

Metabolic

RX

RX

RX


Future 3: Treating the Whole Joint Molecular Stages of Osteoarthritis

BML

Bone marrow lesion

Subchondral

cyst

Synovial thickening,

Effusion

Krasnokutsky, Samuels, et al


Mechanisms recently targeted in drug development
Mechanisms Recently Targeted in Drug Development Molecular Stages of Osteoarthritis

  • MMP/aggrecanase inhibitors

    • Agg-523

      (Wyeth, Phase I)

  • IL-1 antagonist

    • AMG-108 (Amgen, Phase II)

  • iNOS Inhibitor

    • SD6010

      (Pfizer, Phase III)

  • NSAID plus PPI (Astrazeneca)

  • NSAID plus NO (NicOx)

  • Icatibant (Bradykinin B2

    antagonist peptide)

    (Sanofi-Aventis, Phase II)

  • a-NGF ab

    Rinat 624

    (Pfizer, Phase III)

DMOAD

Pain


Regulation of Osteoblast and Osteoclast Activation in the Treatment of Osteoarthritis?

DMOADs?

Bisphosphonate

Calcitonin

Strontium

Cathepsin K


Emerging areas

EMERGING AREAS Treatment of Osteoarthritis?

Genetics

Intra-articular therapy

Tissue Engineering


Intra-articular drug delivery Treatment of Osteoarthritis?

Tissue-specific delivery

Circumvent systemic toxicity

Visco-supplements

Hyaluronic acid

Lubricin

Stimulators of

ECM synthesis

Small molecules

Biologicals

Cells and or

engineered cells

Inhibitors of

ECM degradation

Inflammation

Glucocorticoids


Gene therapy for cartilage repair Treatment of Osteoarthritis?

Chondrocytes

Engineered cell

cDNA

Growth factors:

BMPs, IGFs, FGFs

Transcription factors:

Sox9, Sox6

Signal transduction: Smads

Viral

Engineered cell

MSCs


Future 4 role of genetics in oa
Future 4. Role of Genetics in OA Treatment of Osteoarthritis?

Genetic variations will influence OA:

Phenotype

Susceptibility

Severity

Rate of progression




Summary future directions
Summary: Future Directions Treatment of Osteoarthritis?

OA pain - safe, more effective analgesia

Genetic and biochemical determination of risk for progression

Functional imaging studies of disease activity

Molecular targeting for early intervention

Microsurgical intervention

Cellular tissue repair


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