Non-infectious uveitis (NIU) is an intractable, recurrent, and painful disease that is a common cause of vision loss.
Available treatments of NIU, such as the use of topical corticosteroids, are non-specific and have serious side effects which limits them to short-term use; however, NIU requires long-term treatment to prevent vision loss.
Therefore, a single dose therapeutic that mediates long-term immunosuppression with minimal side effects is desirable.
In order to develop an effective long-term therapy for NIU, an adeno-associated virus (AAV) gene therapy approach was used to exploit a natural immune tolerance mechanism induced by the human leukocyte antigen G (HLA-G).
To mimic the prevention of NIU, naïve Lewis rats received a single intravitreal injection of AAV particles harboring codon-optimized cDNAs encoding HLA-G1 and HLA-G5 isoforms one week prior to the induction of experimental autoimmune uveitis (EAU).
AAV-mediated expression of the HLA-G-1 and -5 transgenes in the targeted ocular tissues following a single intravitreal injection of AAV-HLA-G1/5 significantly decreased clinical and histopathological inflammation scores compared to untreated EAU eyes (p < 0.04).
Thus, localized ocular gene delivery of AAV-HLA-G1/5 may reduce the off-target risks and establish a long-term immunosuppressive effect that would serve as an effective and novel therapeutic strategy for NIU, with the potential for applications to additional ocular immune-mediated diseases.
Investigators have found that 1 intravitreal injection of an adeno-associated virus encoding an immunosuppressive transgene, either HLA-G or eqIL-10, reduced the clinical and histologic inflammation in a well-established model of autoimmune uveitis.
Treating noninfectious uveitis can feel like a losing battle because the available treatments are self-limited because of their adverse effect profile.
Establishing a single-dose treatment that can mediate long-term immunosuppression without hampering the patient with adverse effects would fill an important treatment gap for these patients, according to Brian Gilger, DVM, MS, a professor of ophthalmology at North Carolina State University in Raleigh.
Gilger and colleagues conducted an animal study in rats to evaluate immunomodulatory gene therapy as a long-term treatment for noninfectious uveitis.
They used intravitreal adeno-associated virus (AAV) gene therapy to test the effects of 2 immunomodulatory transgenes, HLA-G and equine IL10 (eqIL10), to treat a rat model of autoimmune uveitis Treatment-naive Lewis rats received either 1 intravitreal injection of 3 uL of saline (control) or AAV particles harboring codon-optimized cDNA encoding HLA-G1 and HLA-G5 or eqIL10 (1e9-1e10 vg) 7 days before autoimmune uveitis was induced.
The animals were then examined daily for 14 days to evaluate the effect of treatment on the degree of inflammation and to measure the aqueous humor cell counts.
In response to the intravitreal injections, from days 10 to 14 after the injections, the investigators observed a significant (P < .05) reduction in the autoimmune uveitis scores and the numbers of aqueous humor cells in the eyes that received active treatment versus control eyes treated with a saline injection.
The histologic inflammatory scores also decreased significantly (P < .05) in the active-treatment eyes compared with the controls.
The results of vector genome biodistribution studies indicated that the AAV vector genomes remained in the ocular tissues; however, a very low neutralizing antibody response was elicited against the AAV capsid, Gilger reported.
Based on their results, the investigators concluded that 1 intravitreal injection of an AAV encoding an immunosuppressive transgene, either HLA-G or eqIL10, significantly reduced the clinical and histologic inflammation in a well-established model of autoimmune uveitis.
They believe that the current results warrant further study of intravitreal delivery of AAV gene therapy for a single-dose treatment of noninfectious uveitis.