Nam Vo, Ph.D. Assistant Professor
University of Pittsburgh
Intervertebral Disc Degeneration:
New concepts and current therapeutic
challenges and opportunities.
TALK OUTLINE
1. Traditional treatments of intervertebral disc degeneration (IDD) & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
TALK OUTLINE
1. Traditional treatments of intervertebral disc degeneration (IDD) & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
Deyo et al. J Am Board Fam Med. 2009
Minimal change in office visits for low back pain since 1990
Increase Utilization
Deyo et al. J Am Board Fam Med. 2009
Self-reported functional limitations, mental health and social limitations worse in 2005 than 1997
Lack of improved outcomes
• Non-operative – Analgesic – Anti-inflammatory – Physical therapy
• Surgery – Fusion – Implant
• Treating symptoms, not cause
Traditional treatment not optimal
Address the underlying pathology/cause
Promote matrix synthesis and/or inhibit catabolic processes
Biologic approaches treating IDD
Matrix loss
Matrix homeostasis
TALK OUTLINE
1. Traditional treatments of IDD & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
TALK OUTLINE
1. Traditional treatments of IDD & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
Molecular Modify metabolism of resident cells
to boost matrix production Cellular
Replace cell loss/defective cells with functional cells
New concepts: preserving disc health
Tissue Replace part or whole disc
(matrix+cells)
Counteract disc matrix loss
• Molecular approaches
– Novel pharmaceuticals
– Gene therapy
• Cellular approaches
– Stem cell therapy
– Alternative cell therapy
• Tissue Approaches
– Scaffolds
– Biomaterials
• Mechanical Approaches
– Rationally Designed Loading
– Preservation of Optimal Biomechanics
New concepts & therapeutic options
• Molecular approaches
– Novel pharmaceuticals
– Gene therapy
• Cellular approaches
– Stem cell therapy
– Alternative cell therapy
• Tissue Approaches
– Scaffolds
– Biomaterials
• Mechanical Approaches
– Rationally Designed Loading
– Preservation of Optimal Biomechanics
New concepts & therapeutic options
Direct protein intradiscal injection…
BMP-2, OP-1, TGF- 1, GDF-5, IGF, FGF
Proteoglycan
Collagen
Thompson et al., Spine 1991 Gruber et al., Exp Cell Res 1997 Osada et al, J Orthop Res 1996 Takegami et al., Spine 2002
Molecular approaches
Kim et al. Spine 2003
BMPs (mainly -2 and -7)
OP-1 (BMP-7) in clinical trial: results unpublished
Direct protein intradiscal injection…
BMP-2, OP-1, TGF- 1, GDF-5, IGF, FGF
Concentration
Time
Proteoglycan
Collagen
Thompson et al., Spine 1991 Gruber et al., Exp Cell Res 1997 Osada et al, J Orthop Res 1996 Takegami et al., Spine 2002
Protein injection not long lasting
Gene Therapy for IDD: a s impler tactic
James Kang
Goal: restore an advantageous balance of anabolic and catabolic metabolism with sustained effect
Molecular approaches: Gene Therapy
CMV Promoter Therapeutic Gene
Constitutive expression
Viral vector
Stab, + Ad-BMP2
Stab, + Saline
MRI T2w at 0, 3, 6, 12 weeks
Gene Therapy: BMP-2
Delay of radiographic progression with Ad-BMP-2 (Shimer et al., ORS 2005)
Proteoglycan increases with Ad-TGF-β1 In Vivo (Nishida et al., 1999. Spine)
Wks: 0 3 6 12
Ad-BMP2
Wks: 0 3 6 12
Saline
Stab
be
d
Gene Therapy: BMP-2
• Molecular approaches
– Novel pharmaceuticals
– Gene therapy
• Cellular approaches
– Stem cell therapy
– Alternative cell therapy
• Tissue Approaches
– Scaffolds
– Biomaterials
• Mechanical Approaches
– Rationally Designed Loading
– Preservation of Optimal Biomechanics
New concepts & therapeutic options
• Molecular approaches
– Novel pharmaceuticals
– Gene therapy
• Cellular approaches
– Stem cell therapy
– Alternative cell therapy
• Tissue Approaches
– Scaffolds
– Biomaterials
• Mechanical Approaches
– Rationally Designed Loading
– Preservation of Optimal Biomechanics
New concepts & therapeutic options
The Problem:
Low cell division, phenotypic shift, decreased metabolic activity
A Potential Solution:
Repopulate the disc with healthy, metabolically active cells
Young
Old
Cell based therapy
MSC
adipocyte
osteocyte chondrocyte
myocyte
tenocyte
stromal cell
•Human bone marrow - Hematopoietic stem cells - Non-hematopoietic
• MSC
Undifferentiated cell (self-renewal)
Mesenchymal stem cell (MSC)
• Co-culture results in MSC differentiation to a more chondrogenic phenotype and stimulation of NP cells – Vadala et al. Spine 2008
• MSCs differentiate into IVD like cells (based on gene expression) when stimulated with TGF-beta – Steck et al. Stem Cells 2005
MSC may restore disc cell population
Sakai et al. Biomaterials 2006
MSC restores disc height and MRI signal
A: Control B: Puncture
0wks 6wks 12wks 0wks 3wks 6wks 12wks
Umbilical derived stem cell therapy
0wks 3wks 6wks 12wks
C: Cells+carrier
• Molecular approaches
– Novel pharmaceuticals
– Gene therapy
• Cellular approaches
– Stem cell therapy
– Alternative cell therapy
• Tissue Approaches
– Scaffolds
– Biomaterials
• Mechanical Approaches
– Rationally Designed Loading
– Preservation of Optimal Biomechanics
New concepts & therapeutic options
TALK OUTLINE
1. Traditional treatments of IDD & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
TALK OUTLINE
1. Traditional treatments of IDD & back pain not optimal
2. New concepts and biologic treatments for IDD
3. Opportunities and challenges
1. Immune response from adenoviral vector
Gene Therapy: safety issues
Challenges: Safety issues with gene therapy
Concern Over Misguided Injections
Intradural therapeutic doses of Ad-TGF and BMP-2 demonstrated no clinical or histologic changes
Supratherapeutic doses of Ad-BMP-2 demonstrated evidence of paralysis or paresthesias, dural fibrosis and fibroblastic infiltration
Wallach et al. Spine 2006; 6:107
Gene therapy using
adeno-associated viral (AAV) vector
more safe than
adenoviral vector (AV)
AAV safer than AV
0 wks 6 wks 12 wks
Control
Stab
0 wks 6 wks 12 wks
AAV2-
BMP2
AAV2-
TIMP1
MRI T2w
AAV gene therapy ( L e c k i e e t a l . , 2 0 1 2 . T S J )
1. Immune response from adenoviral vector
2. Uncontrolled expression of therapeutic gene
CMV Promoter Therapeutic Gene
Constitutive expression
Excessive amount of therapeutic protein!
BMP
Osteophyte formation Neurological complication Cancer (Carragee et al., ISSLS 2012)
Gene Therapy: safety issues
Also need a titratable “on” switch Control through use of activator compounds without human activity
RheoSwitch Mammalian Inducible Expression system (Intrexon, VA)
Improved Safety Through Control of Gene Expression
Inducible systems: tet-off mechanisms
transcription
GENE OF INTEREST TRE P pA
tTA
GENE OF INTEREST TRE P pA
tTA transcription +TC Vadala et al.
Spine 2007
RheoSwitch Mammalian Inducible Expression system (Intrexon, VA)
Improved safety through regulated expression
VIRUS ONLY
VIRUS + LIGAND
L2-3 L3-4 L4-5
5 DAYS POST-LIGAND
No GFP expression was evident in the adjacent discs, spinal cord, dura, bone, liver, or brain of any animals
Sowa et al. Spine 2011
Challenges: Safety issues with cell therapy
Vadala et al. J Tissue Eng Regen Med. 2012
Mesenchymal stem cells injection in degenerated disc: cell leakage may induce osteophyte formation
• Haufe et al. Stem Cells Dev. 2006
– Case series of 10 patients with provocative discography, axial back pain
– Injection of BM derived MSCs
– One year follow up demonstrating no improvement in symptoms
Cell therapy: human a different beast
Human studies
Access and need for multiple procedures Carragee et al. ISSLS Prize 2009
Timing of interventions Prior to end-stage anatomic disc disease
Hostile IVD environment and safety
Current limitations and remaining questions
Access and need for multiple procedures Carragee et al. ISSLS Prize 2009
Timing of interventions Prior to end-stage anatomic disc disease
Hostile IVD environment and safety
Attention to treating the pain component
Current limitations and remaining questions
Effects of GDF-5 treatment in animal model of IDD
– Improved disc height, T2 weighted signal, histological changes, and GAG content
– Suppressed mRNA expression of… • IL-1beta, IL-6, TNF-alpha (inflammatory mediators) • ADAMTS-4, COX-2 (catabolic enzymes) • NGF, VEGF (pain related markers)
Clinical success may require specific attention to modulating PAIN!
Liang et al. Spine J. 2009 Nov 17 Masuda et al. ISSLS 2009
Access and need for multiple procedures Carragee et al. ISSLS Prize 2009
Timing of interventions
Hostile IVD environment and safety
Attention to treating the pain component
Need for further elucidation of key pathways
Current limitations and remaining questions
Molecular Modify metabolism of resident cells
to boost matrix production Cellular
Replace cell loss/defective cells with functional cells
New biologics for preserving disc health
Tissue Replace part or whole disc
(matrix+cells)
Specific pathway
•DNA damage •Oxidative stress
•NF- B
Access and need for multiple procedures Carragee et al. ISSLS Prize 2009
Timing of interventions
Hostile IVD environment and safety
Attention to treating the pain component
Need for further elucidation of key pathways
Biologic approaches should be viewed with cautious optimism
Current limitations and remaining questions
University of Pittsburgh Hillman Cancer Institute
Laura Niedernhofer Paul Robbins Jeremy Tilstra Andria Robison Cheryl Clauson
Ferguson Laboratory of Orthopaedics Research
James Kang (Director) Gwen Sowa Nam Vo
Luigi Nasto Fabrizio Russo, Hyoung-Yeon Seo Kevin Ngo, Qing Dong Takashi Yurube, Robert Hartman, Wan Huang, Paulo
Coelho, Kevin Bell
Funding Sources
The Pittsburgh Foundation UPMC Department of Orthopaedics Surgery
Orthopaedic Research and Education Foundation AOSpine North America Young Investigators Research Grant
“BioSpina” Italian Spine Society Research Grant NIH (R21 AG033046), NIH (ES016114)
Acknowledgements
Dept of Orthopaedic Surgery, Catholic University of Rome, Italy
Thank you!
Urban et al. 2004
Barriers: Discs have limited nutrition and capacity for repair
Human studies
• Yoshikawa et al. Spine 2010 – Case report of two patients
– Low back pain, radicular
symptoms, lack of response to conservative therapy
– Symptom improvement seen 2 yrs after collagen sponge containing autologous MSCs were grafted into degenerated discs
Cell therapy: human a different beast
Goal: restore an advantageous balance of anabolic and catabolic metabolism with sustained effect
In Vivo Approach: single procedure, low efficiency
Ex Vivo Approach: no host exposure to virus, requires cell source
Molecular approaches: Gene Therapy
Other treatments
• NBD peptide
• N-link protein peptide
• Glucosamine
• Omega-3 fatty acid
• Platelet rich plasma (PRP)
Articular chondrocytes transduced with ad-BMP and co-cultured with NP cells increased proteoglycan and collagen
Implications for improving native NP cell matrix production while providing the disc with metabolically active chondrocytes
Zhang et al. Spine 2005;30(23):2601.
Cell therapy with Ex Vivo gene therapy
Stimulation of differentiation or progenitor cells NP cells show chondrogenic/osteogenic phenotypes in vitro
Notochordal cells
EUROdisc use of autologous cells from herniated NP Meisel, Biomol Eng 2007
Synovium derived mesenchymal stem cells
Adipose derived stem cells
Combine cell based therapy with ex vivo gene therapy Zhang et al. Spine 2005, 2008
Immortalization to increase cell lifespan and increase matrix (concerns regarding oncogenesis)
Chung et al. Spine 2007
Alternative cell-based therapy approaches
RheoSwitch Mammalian Inducible Expression system (Intrexon, VA)
o An insect pheromone receptor, whose synthetic ligand has no pleiotropic effects in mammalian cells and exhibits no cross talk with endogenous transcription factors…limiting potential toxicity in humans.
o Inducible and adjustable control (0-10000x) of gene expression. No leaky basal expression
polyA GENE Preg polyA Gal4-EcR IRES PUbC VP16-RXR
RG-115830
Just because it is “natural” doesn’t mean it is safe!
Disc Loading in vivo • Traumatic forces result
in matrix degradation1
• Inflammatory and mechanical signaling linked
• The most serious spine pathology relates to the highest and lowest degrees of physical activity (Videman et al. Spine 1990)
1Guerhing et al., Spine 2005; 30(22): 2510.
Evidence for the Beneficial Effects of Motion
• Lack of effectiveness of bed rest – Deyo et al, NEJM 1986
• Motion sparing technology • Both tensile and compressive loading have been
shown to be anti-catabolic and anti-inflammatory in vitro – Sowa et al. JOR 2011; Sowa et al. Spine J. 2011
Regenerative Rehabilitation
control 6% tensile strain
Inflammatory stimulus
Inflammatory stimulus + 6% tensile strain
C o l l a g e n P r o t e o g l y c a n s
P T T
Heinegard et al., 2005
Load is resisted by bouncing ball-like structures (PG) retained in a network of rope-like collagen fibers
Normal
Degenerated
Construction
quality &
maintenance
GENETICS
(faulty)
MECHANICAL
(trauma)
Excessive loads (sudden)
ENVIRONMENTAL smoking
nutrition
occupation
Assaults radiation
wind
current
Time-dependent
wears and tears (slow)
AGING (time-dep damage of
macromolecules)
POSSIBLE CAUSES OF BREAKDOWN OF A BRIDGE: AN ANALOGY TO DISC DEGENERATION
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