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Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann
S Prabhakar1, G J Brenner, B Sung
1Neuroscience Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Abstract:
Schwannomas are benign tumors forming along peripheral nerves that can cause deafness, pain and paralysis. Current treatment involves surgical resection, which can damage associated nerves. To achieve tumor regression without damage to nerve fibers, we generated an HSV amplicon vector in which the apoptosis-inducing enzyme, caspase-1 (ICE), was placed under the Schwann cell-specific P0 promoter. Infection of schwannoma, neuroblastoma and fibroblastic cells in culture with ICE under the P0 promoter showed selective toxicity to schwannoma cells, while ICE under a constitutive promoter was toxic to all cell types. After direct intratumoral injection of the P0-ICE amplicon vector, we achieved marked regression of schwannoma tumors in an experimental xenograft mouse model. Injection of this amplicon vector into the sciatic nerve produced no apparent injury to the associated dorsal root ganglia neurons or myelinated nerve fibers. The P0-ICE amplicon vector provides a potential means of 'knifeless resection' of schwannoma tumors by injection of the vector into the tumor with low risk of damage to associated nerve fibers.
Insights
This study developed a novel gene therapy using a P0 promoter-driven caspase-1 (ICE) amplicon vector for targeted schwannoma treatment. This approach offers a potential
Area of Science:
- Oncology
- Gene Therapy
- Neuroscience
Background:
- Schwannomas are benign peripheral nerve tumors causing significant neurological deficits.
- Current surgical resection risks nerve damage and associated functional loss.
- Novel therapeutic strategies are needed for nerve-sparing schwannoma treatment.
Purpose of the Study:
- To develop a gene therapy vector for selective schwannoma regression.
- To utilize the Schwann cell-specific P0 promoter for targeted delivery of an apoptosis-inducing enzyme.
- To evaluate the efficacy and safety of this 'knifeless resection' approach.
Main Methods:
- Generation of an HSV amplicon vector expressing caspase-1 (ICE) under the P0 promoter.
- In vitro assessment of selective toxicity in schwannoma, neuroblastoma, and fibroblastic cell lines.
- In vivo evaluation of intratumoral P0-ICE amplicon vector injection in a xenograft mouse model.
- Assessment of sciatic nerve injury following vector administration.
Main Results:
- The P0 promoter selectively targeted schwannoma cells, inducing apoptosis.
- ICE under a constitutive promoter showed non-specific toxicity.
- Intratumoral injection of the P0-ICE vector led to significant schwannoma tumor regression in mice.
- No apparent injury to sciatic nerve fibers or dorsal root ganglia neurons was observed.
Conclusions:
- The P0-ICE amplicon vector demonstrates selective toxicity towards schwannoma cells.
- This gene therapy approach achieves significant tumor regression with minimal risk to nerve fibers.
- The P0-ICE amplicon vector represents a promising 'knifeless resection' strategy for schwannoma treatment.
