6/4/2011 1 Translational Studies In Spinal Cord Injury: An Update Translational Studies In Spinal Cord Injury: An Update Alexander R. Vaccaro, MD, PhD, FACS Professor, Vice Chairman Department of Orthopaedics and Neurosurgery Thomas Jefferson University and the Rothman Institute Philadelphia, PA Disclosure Disclosure Grant Support/ Royalties/stock options: Depuy, Medronics, Stryker, Globus, Stout Medical, Progressive Spinal Technologies, Aesculap, Alphatec, Biomet Spine, Paradigm Spine, Replication Medica, Spinology, Orthofix, Bonovo Spine, Gamma Spine, LBI, SBI, Orthovita, K2M, Cerapedics • Novel methods to reduce the secondary SCI are of great interest • Why? • Regaining even modest control of extremity function can have a dramatic effect on quality of life Pathophysiology • Secondary Injury • Ischemia-reperfusion • Free-radical formation • Calcium influx • Inflammatory cell recruitment
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6/4/2011
1
Translational Studies In Spinal Cord Injury:
An Update
Translational Studies In Spinal Cord Injury:
An Update
Alexander R. Vaccaro, MD, PhD, FACSProfessor, Vice Chairman
Department of Orthopaedics and NeurosurgeryThomas Jefferson University
and the Rothman InstitutePhiladelphia, PA
DisclosureDisclosure� Grant Support/ Royalties/stock options:
Physical therapy •Low-level LASER (light amplification by stimulated emission of radiation) therapy•Oscillating field stimulator•Functional electrical stimulation•Repetitive transcranial magnetic stimulation
Pharmacological and physiatric stimulation of the spinal central pattern generator (CPG)
Local hypothermia
Hyperbaric oxygen therapy
Combinatory (‘COMBO’) strategies
Cell adhesion molecules (L1-CAM)
DMSO (dimethyl sulfoxide)
Erythropoietin
Melatonin
Inosine (Axosine)
AIT-082 (leteprinim potassium, Neotrofin)
4-aminopyridine (Fampridine)
Riluzole
Fusion technology (polyethylene glycol)
Physical therapy •Low-level LASER (light amplification by stimulated emission of radiation) therapy•Oscillating field stimulator•Functional electrical stimulation•Repetitive transcranial magnetic stimulation
Pharmacological and physiatric stimulation of the spinal central pattern generator (CPG)
Local hypothermia
Hyperbaric oxygen therapy
Combinatory (‘COMBO’) strategies
SCI Translational Studies Therapeutic Approaches Currently In or About to Begin Human Evaluation
TherapyTherapyCommercial
SponsorCommercial
Sponsor Therapeutic ApproachTherapeutic Approach Study DesignStudy Design StatusStatus
Anti-Nogo AntibodiesAnti-Nogo Antibodies
Cethrin®Cethrin®
MinocyclineMinocycline
NovartisNovartis
Aiseres Pharmaceuticles
Aiseres Pharmaceuticles
NoneNone
Inhibit activity of Nogo-A, an inhibatory constituent within CNS myelin that impedes axonal regeneration and/or sprouting
Inhibit activity of Nogo-A, an inhibatory constituent within CNS myelin that impedes axonal regeneration and/or sprouting
Cethrin (BA-210) inhibits rho, a small GTPase that has an important role in mediating axonal growth and neuronal apoptosis.
Cethrin (BA-210) inhibits rho, a small GTPase that has an important role in mediating axonal growth and neuronal apoptosis.
Minocycline attenuates neuro-inflammation and inhibits apoptosis.
Minocycline attenuates neuro-inflammation and inhibits apoptosis.
• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated 7-14 days post-injury.• Antibody administered via intrathecal infusion over weeks, or via repeated bolus intrathecal injection
• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated 7-14 days post-injury.• Antibody administered via intrathecal infusion over weeks, or via repeated bolus intrathecal injection
• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 7 days post-inury.• Cethrin applied to the overlying dura at the time of spinal cord decompression
• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 7 days post-inury.• Cethrin applied to the overlying dura at the time of spinal cord decompression
• Complete and incomplete thoracic and cervical SCI in a single center, randomized, clinical trial (Univ of Calgary).• Treatment initiated within 12 hours of injury.• Minocycline intravenously administered twice a day for 1 week.
• Complete and incomplete thoracic and cervical SCI in a single center, randomized, clinical trial (Univ of Calgary).• Treatment initiated within 12 hours of injury.• Minocycline intravenously administered twice a day for 1 week.
Study began in 2006, currently 45 patients enrolled.
Study began in 2006, currently 45 patients enrolled.
Study began in 2005 and completed in 2007, with results in submission. Subsequent prospective randomized study being planned.
Study began in 2005 and completed in 2007, with results in submission. Subsequent prospective randomized study being planned.
Study began in 2004 and has recruited over 50 patients. Preliminary results in submission. Subsequent prospective randomized study being planned.
Study began in 2004 and has recruited over 50 patients. Preliminary results in submission. Subsequent prospective randomized study being planned.
6/4/2011
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Continued…
RiluzoleRiluzole
Magnesium (NeuroShield)Magnesium
(NeuroShield)
Human Embryonic Stem
Cell Derived Oligodendrocyte
Progenitors
Human Embryonic Stem
Cell Derived Oligodendrocyte
Progenitors
NoneNone
MedtronicMedtronic
GeronGeron
Riluzole is a sodium channel blocker that is currently FDA approved for the treatment of ALS.
Riluzole is a sodium channel blocker that is currently FDA approved for the treatment of ALS.
Magnesium is a physiologic antagonist to NMDA receptorsMagnesium is a physiologic antagonist to NMDA receptors
hESC-oligodendrocyte progenitors are to re-myelinate demyelinated axons and restore conduction.
hESC-oligodendrocyte progenitors are to re-myelinate demyelinated axons and restore conduction.
• ASIA A, B and C thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• Riluzole to be administered orally twice per day for a week.
• ASIA A, B and C thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• Riluzole to be administered orally twice per day for a week.
• Phase I saftey study in humans complete. ASIA A cervical SCI to be recruited in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• NeuroShield to be administered intravenously over 24 hours.
• Phase I saftey study in humans complete. ASIA A cervical SCI to be recruited in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• NeuroShield to be administered intravenously over 24 hours.
• ASIA A thoracic SCI in a multicenter, non-randomized, clinical trial.• Transplantation to occur 7-14 days post-injury. • Cells can be injected into the injured spinal cord.
• ASIA A thoracic SCI in a multicenter, non-randomized, clinical trial.• Transplantation to occur 7-14 days post-injury. • Cells can be injected into the injured spinal cord.
Initiated as a multicenter collaboration through the North American Clinical Trials Network.
Initiated as a multicenter collaboration through the North American Clinical Trials Network.
Phase I safety study in healthy volunteers now completed; SCI study set to begin
Phase I safety study in healthy volunteers now completed; SCI study set to begin
FDA approval granted in January 2009, clinical hold released August 2010
FDA approval granted in January 2009, clinical hold released August 2010
Systemic Hypothermia
Systemic Hypothermia
NoneNone
Hypothermia slows metabolic rate, reduces inflammation and oxidative stress
Hypothermia slows metabolic rate, reduces inflammation and oxidative stress
• Retrospective review of 14 ASIA A cervical SCI in a single center (Univ of Miami)• Treatment initiated within 12 hours of injury in almost all patients• Systemic hypothermia induced to 33°C for 48 hours
• Retrospective review of 14 ASIA A cervical SCI in a single center (Univ of Miami)• Treatment initiated within 12 hours of injury in almost all patients• Systemic hypothermia induced to 33°C for 48 hours
Study initiated in 2006. Review of 14 ASIA A patients suggests that the treatment is safe, and in 6 of 14 improved to ASIA B, C, or D.
Study initiated in 2006. Review of 14 ASIA A patients suggests that the treatment is safe, and in 6 of 14 improved to ASIA B, C, or D.
Hypothermia
• September, 2007• Kevin Everett C3-4 Fx/Dl
• 1970’s
• Performed at several centers after acute SCI
• Poor study designs, few patients, limited outcome measures
• 8 small case series (last in 1984) heterogeneous pop, no control
Hypothermia
• Decreases tissue metabolism and energy requirements Zager J. Neuro 1988
• Decreases swelling of Parenchyma and nerve roots Huang, J. Neuro. Science 1999
• Reduces tissue hemorrhage Albin J. Trauma 1969, Yu, J. Neuro, 2000