Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy
Open accessAbstract
Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.
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Hydroxychloroquine inhibits viral particle recognition by TLR and cGAS.
“Another approach consists of proteasome inhibitors, such as carfilzomib and bortezomib, limiting rAAV degradation and antibody presentation; and hydroxychloroquine, inhibiting viral particle recognition by TLR and cGAS [12,[133][134][135].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [12]
Proteasome inhibitors such as carfilzomib and bortezomib limit rAAV degradation and antibody presentation.
“Another approach consists of proteasome inhibitors, such as carfilzomib and bortezomib, limiting rAAV degradation and antibody presentation; and hydroxychloroquine, inhibiting viral particle recognition by TLR and cGAS [12,[133][134][135].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [12]
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Prasad, S., Dimmock, D. P., Greenberg, B., Walia, J. S., Sadhu, C., Tavakkoli, F., & Lipshutz, G. S. (2022) · Human Gene Therapy · doi:10.1089/hum.2022.138 · Cited by 81 · see citing works
Risk mitigation of immunogenicity: a key to personalized retinal gene therapy
Varin, J., Morival, C., Maillard, N., Adjali, O., & Cronin, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312818 · Cited by 19 · see citing works
- Authors
- Chandler, L., Yusuf, I., McClements, M., Barnard, A., MacLaren, R., & Xue, K.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Chandler, Laurel
- Xue, Kanmin
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-07-14
- Volume
- 21
- Issue
- 14
- Pages
- 4972
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7404262
- OpenAlex
- W3043141198
- Cited by
- 49
- References
- 147
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 1
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fight for Sight UK (5039/5040)
- Wellcome Trust (216593/Z/19/Z)
- Academy of Medical Sciences (SGL016\1034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Drug-Induced Ocular Toxicity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- hydroxychloroquine, chloroquine, immunomodulation, retinal gene therapy, adeno-associated virus vectors, viral infection, TLR9, cGAS, nucleic acid sensors, HIV, SARS-CoV-2, antimalarial drugs
- MeSH terms
- Betacoronavirus, SARS-CoV-2, Dependovirus, Animals, Chloroquine, Humans, Hydroxychloroquine, Retinal Diseases, Virus Diseases, Genetic Therapy, Immunomodulation
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