Gene Therapy Preserves Retinal Function in Dog Model of Batten

Results support further testing of eye therapy for Batten children

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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A single intravitreal injection — into the vitreous cavity, in the back of the eye — of a gene therapy was found to preserve the function and structure of the retina in a dog model of late infantile Batten disease.

Eye inflammation was the only side effect of the therapy, and it was responsive to medication, the study reported.

“Taken together, these data support further testing of ocular gene therapy as an adjunct treatment to [central nervous system]-targeting therapy to prevent progressive vision loss in children with CLN2 disease,” the researchers wrote. Late infantile Batten disease is also known as CLN2 disease.

The study, “Intravitreal gene therapy preserves retinal function in a canine model of CLN2 neuronal ceroid lipofuscinosis,” was published in the journal Experimental Eye Research

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2 Late Infantile Batten Disease Gene Therapies Move to Human Trials

Testing the use of gene therapy to preserve retinal function

CLN2 disease is characterized by mutations in the TPP1 gene, which provides instructions to produce an enzyme called tripeptidyl peptidase1 (TPP1).

These mutations cause decreased or absent enzymatic activity, which affects protein waste disposal and triggers cell death, contributing to symptoms such as vision loss. 

To combat this, researchers have been studying whether delivering a functional TPP1 enzyme using gene therapy could address the disease manifestations. In fact, TPP1 replacement therapy has shown benefits in treating neurological and visual alterations in a dog CLN2 disease model.

Ultimately, these discoveries led to a successful clinical trial of TPP1 enzyme replacement delivered via infusion into the cerebrospinal fluid — the liquid surrounding brain and spinal cord — and the approval of Brineura (cerliponase alfa) by the U.S. Food and Drug Administration (FDA).

However, this treatment approach requires frequent and lifelong administrations to both the brain and the eye and thus carries a significant burden for patients and their families.

Now, in a dog model of CLN2 disease, a research team in the U.S. investigated whether a single injection of gene therapy could be a long-term source of TPP1 and preserve vision.

Previous research had shown that administration of a viral vector carrying the TPP1 gene into fluid-filled cavities in the brain resulted in significant delays in the onset and progression of neurological signs in a dog model of CLN2 disease. However, it did not inhibit disease-related degeneration of the retina, a thin layer of tissue on the inside back wall of the eye.

In the study, the animals received a single intravitreal injection of the gene therapy in the left eye at nearly four months of age. On the right eye, they were given a vector without the human TPP1 (hTTP1) gene to serve as a control.

Specifically, the vector was an adeno-associated virus 2 (AAV2), which is “a vector of choice for retinal gene therapy trials and is used in the only FDA-approved retinal gene therapy, Voretigene neparvovec,” the researchers wrote. Voretigene neparvovec is sold as Luxturna for the treatment of inherited retinal disease.

Eye examinations were performed one day and one week after injection, and then monthly and as needed.

Imaging analysis showed stable, widespread gene expression (activity) of TPP1 throughout the inner retina.

These results suggest that ocular … gene therapy is likely to be effective in preserving retinal function in children with CLN2 disease, even when administered after the onset of a decline in retinal function.

At a structural and functional level, the researchers found that the single gene therapy injection prevented disease-related declines and suppressed cell loss in the inner and outer nuclear layers of the retina for at least six months. The animals were killed at nearly 10 months of age when they reached end-stage neurological disease.

CNL2 disease in these dogs (Dachshunds) is marked by a progressive thinning of the retina. With the therapy, a significant inhibition of this thickness decrease was found when comparing treated with control eyes.

Intraocular (eye) inflammation was found in all treated eyes at 6–17 weeks post-treatment, but in none of the control eyes. According to the researchers, “the putative presence of anti-hTPP1 antibodies at higher concentrations in the eyes treated with the hTPP1 vector than in the contralateral eyes suggests that the treatment-related inflammation was mediated by an immune response to hTPP1.”

“The delay in the onset of inflammation,” they added, “is also more consistent with continued production of hTPP1 than with capsid concentration which would be present immediately after injection and quickly decline.” Capsids are protein structures where viral genetic material is packaged.

This adverse reaction was the only one found and was responsive to medication provided during the study.

“The anti-inflammatory protocols developed in the dog model may be adaptable to human [patients] who exhibit intraocular inflammation secondary to retinal gene therapy treatments,” the researchers wrote.

Overall, “these results suggest that ocular AAV2-mediated hTPP1 gene therapy is likely to be effective in preserving retinal function in children with CLN2 disease, even when administered after the onset of a decline in retinal function,” the investigators wrote.