AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery

Koponen, Sanna; Kokki, Emmi; Tamminen, Toni; Ylä‐Herttuala, Seppo

doi:10.3389/fddev.2023.1148795

Cited by 4 publications

References 76 publications

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H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Bernardo-Colón,

Bighinati,

Parween

et al. 2024

Preprint

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Photoreceptor death causes blinding inheritable retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, finding effective treatments is urgent. This study focuses on developing a targeted approach by evaluating the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), known to restrict common cell death pathways associated with retinal diseases. Peptides with affinity for the PEDF receptor, PEDF-R, (17-mer and H105A) delivered via eye drops reached the retina, efficiently promoted photoreceptor survival, and improved retinal function in RP mouse models based on both therd10mutation and the rhodopsin P23H mutation. Additionally, intravitreal delivery of AAV-H105A vectors delayed photoreceptor degeneration in the latter RP mouse model. Furthermore, peptide H105A specifically prevented photoreceptor death induced by oxidative stress, a contributing factor to RP progression, in human retinal organoids. This promising approach for peptide eye drop delivery holds significant potential as a therapeutic for preventing photoreceptor death in retinal disorders, offering a high safety profile, low invasiveness and multiple delivery options.One Sentence SummaryNeurotrophic PEDF peptides delivered as eye drops preserve photoreceptor viability, morphology, and function in models of human retinal diseases.

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H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Bernardo-Colón,

Bighinati,

Parween

et al. 2024

Preprint

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Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration

Liu,

Copland,

Clare

et al. 2024

Sci. Transl. Med.

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Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3 , which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3 -knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)–expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3 -knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

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Recent advances in various adeno-associated viruses (AAVs) as gene therapy agents in hepatocellular carcinoma

Hadi,

Qutaiba B. Allela,

Jabari

et al. 2024

Virol J

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Primary liver cancer, which is scientifically referred to as hepatocellular carcinoma (HCC), is a significant concern in the field of global health. It has been demonstrated that conventional chemotherapy, chemo-hormonal therapy, and conformal radiotherapy are ineffective against HCC. New therapeutic approaches are thus urgently required. Identifying single or multiple mutations in genes associated with invasion, metastasis, apoptosis, and growth regulation has resulted in a more comprehensive comprehension of the molecular genetic underpinnings of malignant transformation, tumor advancement, and host interaction. This enhanced comprehension has notably propelled the development of novel therapeutic agents. Therefore, gene therapy (GT) holds great promise for addressing the urgent need for innovative treatments in HCC. However, the complexity of HCC demands precise and effective therapeutic approaches. The adeno-associated virus (AAV) distinctive life cycle and ability to persistently infect dividing and nondividing cells have rendered it an alluring vector. Another appealing characteristic of the wild-type virus is its evident absence of pathogenicity. As a result, AAV, a vector that lacks an envelope and can be modified to transport DNA to specific cells, has garnered considerable interest in the scientific community, particularly in experimental therapeutic strategies that are still in the clinical stage. AAV vectors emerge as promising tools for HCC therapy due to their non-immunogenic nature, efficient cell entry, and prolonged gene expression. While AAV-mediated GT demonstrates promise across diverse diseases, the current absence of ongoing clinical trials targeting HCC underscores untapped potential in this context. Furthermore, gene transfer through hepatic AAV vectors is frequently facilitated by GT research, which has been propelled by several congenital anomalies affecting the liver. Notwithstanding the enthusiasm associated with this notion, recent discoveries that expose the integration of the AAV vector genome at double-strand breaks give rise to apprehensions regarding their enduring safety and effectiveness. This review explores the potential of AAV vectors as versatile tools for targeted GT in HCC. In summation, we encapsulate the multifaceted exploration of AAV vectors in HCC GT, underlining their transformative potential within the landscape of oncology and human health.

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AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery

Cited by 4 publications

References 76 publications

H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration

Recent advances in various adeno-associated viruses (AAVs) as gene therapy agents in hepatocellular carcinoma

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