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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

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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)


Future directions

A

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(R. Regatte, NYUHJD, unpublished data)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 heterogeneous etiologies

…which develops over decades

Future 2: OA Phenotypes


Oa phenotype understanding early molecular mechanisms

OA “Phenotype”: Understanding Early Molecular Mechanisms

Aging processes

Genetic susceptibility

Mechano-transduction

Cartilage Biology

Bone biology

Synovial events

Metabolic events


Oa phenotype disease mechanisms

OA Phenotype & Disease Mechanisms

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 in 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 directions

Future 3: Treating the Whole Joint

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

  • 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


Future directions

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

DMOADs?

Bisphosphonate

Calcitonin

Strontium

Cathepsin K


Emerging areas

EMERGING AREAS

Genetics

Intra-articular therapy

Tissue Engineering


Future directions

Intra-articular drug delivery

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


Future directions

Gene therapy for cartilage repair

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

Genetic variations will influence OA:

Phenotype

Susceptibility

Severity

Rate of progression


Future directions

Valdes and Spector, 2009; Med. Clin. N. Am 93:45-66


Future directions

Valdes and Spector, 2009; Med. Clin. N. Am 93:45-66


Summary future directions

Summary: Future Directions

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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