Retinal function and structure are preserved in a canine model of CLN2 disease after intravitreal implantation of stem cells genetically modified to overproduce TPP1 enzyme

Abstract

Purpose : CLN2 disease is an inherited, childhood disorder which causes progressive vision loss, and cognitive and neurological dysfunction. Dogs with CLN2 disease exhibit similar clinical signs including progressive retinal degeneration, beginning at 4 to 5 months of age, characterized by significantly reduced electroretinogram (ERG) b-wave amplitudes and multi-focal retinal detachments. CLN2 disease results from lack of the lysosomal enzyme, TPP1. Studies were performed to determine whether supplying the deficient TPP1 enzyme with intravitreal ex vivo gene therapy can prevent retinal degeneration in CLN2-affected dogs.

Methods : Autologously derived mesenchymal stem cells (MSCs) from CLN2-affected Dachshunds (n=5) were transduced with adeno-associated virus (AAV2)-packaged DNA constructs that direct stable overexpression and secretion of TPP1 or stable expression of green fluorescent protein (GFP). TPP1-transduced cells were implanted into the vitreous of one eye and GFP-transduced cells into the contralateral eye at 3 months of age. Thereafter, dogs were evaluated monthly with bilateral ERG and in vivo retinal imaging until near end-stage neurologic disease was reached around 10 months of age.

Results : For each dog, the eye treated with TPP1-expressing MSCs had better preserved retinal function and structure compared to the control eye, which had deficits typical of untreated CLN2 disease. Treatment delayed the onset of ERG amplitude decline by 1 to 2 months and reduced the rate of decline thereafter by an average of 41% (range: 23% to 67%) compared to that of the control eye. The control retina developed extensive detachment lesions in 4 of 5 dogs, while lesions were fully prevented in 2 of the contralateral TPP1-treated eyes and greatly reduced in the remaining treated eyes.

Conclusions : We have demonstrated the potential to inhibit retinal degeneration with a continuous supply of therapeutic compound produced by autologous, genetically modified stem cells that have been implanted into the vitreous. This approach to therapeutic drug delivery offers a long-term treatment and is applicable to many other hereditary retinal degenerative diseases.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

TPP1-expressing MSCs preserve retinal structure. In a 7-month-old dog, 23% of the control retina exhibits detachment lesions, while lesions are fully prevented in the TPP1-treated retina.