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bcl-2 gene therapy exacerbates excitotoxicity.

P D Simon¹, C K Vorwerk, S S Mansukani

¹Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia 19104, USA.

Human Gene Therapy

|July 31, 1999

Summary

The protooncogene BCL-2 gene therapy, intended to prevent neuronal death, unexpectedly increased susceptibility to injury in rat retinal ganglion cells. This study found BCL-2 transduction had a harmful effect, contrary to expectations for neuroprotection.

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Area of Science:

Neuroscience
Molecular Biology
Ophthalmology

Background:

The BCL-2 protooncogene inhibits neuronal apoptosis and exogenous insults.
BCL-2 is a potential therapeutic target for preventing excitotoxic neuronal death.
Gene therapy using viral vectors offers a method for in vivo gene delivery.

Purpose of the Study:

To investigate the neuroprotective potential of BCL-2 gene delivery in the retina.
To determine if BCL-2 transduction protects retinal ganglion cells from excitotoxicity.
To evaluate BCL-2 gene therapy as a potential in vivo therapeutic strategy.

Main Methods:

Adeno-associated viral vectors were used to deliver the BCL-2 gene.
The BCL-2 gene was introduced into the ganglion cell layer of rat retinas.

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Retinal ganglion cells were subsequently subjected to axonal injury and NMDA-induced excitotoxicity.

Main Results:

Contrary to the hypothesis, BCL-2 gene transduction did not protect retinal ganglion cells.
BCL-2 transduction significantly increased ganglion cell susceptibility to axonal injury.
Retinal ganglion cells infected with BCL-2 showed heightened vulnerability to NMDA excitotoxicity.

Conclusions:

BCL-2 gene transduction in the retina demonstrated a deleterious effect on ganglion cells.
The study challenges the therapeutic potential of BCL-2 gene therapy for excitotoxic injury in the retina.
Further research is needed to understand the mechanisms behind BCL-2's detrimental effects in this context.