Hyperuricemia (HU) is a metabolic disease caused by high serum uric acid (SUA) levels due to insufficient renal excretion, excessive production, or insufficient intestinal excretion. Various conventional treatments are commonly used to treat HU, such as valproic acid and allopurinol (xanthine oxidase inhibitor). Valproic acid increases urination, thereby enhancing the excretion of urate crystals, while allopurinol relieves symptoms by reducing uric acid production by inhibiting xanthine oxidase. However, increased urination increases the excretion of urate crystals, leading to kidney damage.
Meanwhile, reduced production of uric acid (UA) may cause hypouricemia, thereby interfering with the body's normal metabolic function. Similarly, recombinant pegloticase, a mammalian uricase (pegloticase), has also been widely used to enzymatically hydrolyze UA to allantoin. However, pegloticase has the disadvantage of immunogenicity, and it also produces anti-pegloticase antibodies, increased drug clearance, loss of efficacy, and infusion reactions. In addition, clinical experience has shown that patients treated with pegloticase are more likely to suffer from gout attacks.
Protein and enzyme replacement therapies are delivered via nucleic acid (mRNA, DNA, etc.) or direct protein delivery. However, mRNA-mediated protein expression has several potential advantages over protein therapy for replacing therapeutic proteins. Delivery of mRNA promotes transient protein expression in the cytoplasm, thereby bypassing nuclear entry and limiting genomic integration. mRNA is neither a final product nor genetic information, and mRNA is a rapid turnover. Therefore, this provides great flexibility for therapeutic mRNA to expand its application range.
However, due to mRNA instability and deprivation of intracellular internalization, rapid mRNA degradation limits the clinical application of mRNA therapeutics. Delivery of mRNA using viral vectors may modulate transgene expression due to the risk of abnormal vector integration. Therefore, non-viral mRNA delivery methods allow transient protein expression to avoid the risk of genomic integration associated with viral vectors. To address this issue, ionizable lipids or lipidoids can form different delivery platforms with mRNA, such as lipid nanoparticles (LNPs) and liposomes. Several ionizable lipids and cationic lipids have been reported for nucleic acid delivery.
| Cat.No. | Product Name | Price |
|---|---|---|
| PMCRL-0001 | EGFP circRNA-LNP | Inquiry |
| PMCRL-0002 | Firefly Luciferase circRNA-LNP | Inquiry |
| PMCRL-0003 | Gaussia Luciferase circRNA-LNP | Inquiry |
| PMCRL-0004 | Renilla Luciferase circRNA-LNP | Inquiry |
| PMCRL-0005 | mCherry circRNA-LNP | Inquiry |
| PMCRL-0017 | Oct4 circRNA-LNP | Inquiry |
| PMmRNL-0001 | EGFP mRNA-LNP | Inquiry |
| PMmRNL-0002 | mCherry mRNA-LNP | Inquiry |
| PMmRNL-0003 | Firefly Luciferase mRNA-LNP | Inquiry |
| PMmRNL-0004 | Cas9-HA mRNA-LNP | Inquiry |
| PMmRNL-0005 | EGFP mRNA (no modificaiton)-LNP | Inquiry |
| PMmRNL-0006 | mCherry mRNA (no modificaiton)-LNP | Inquiry |
| PMmRNL-0007 | Firefly Luciferase mRNA (no modificaiton)-LNP | Inquiry |
| PMmRNL-0008 | spCas9 mRNA (no modificaiton)-LNP | Inquiry |
| PMmRNL-0009 | spCas9 mRNA (N1-Me-Pseudo UTP modified)-LNP | Inquiry |
| PMmRNL-0010 | SARS COV-2 Spike Protein (Alpha Variant) mRNA-LNP | Inquiry |
Recently, researchers from the School of Life Sciences of Beijing Institute of Technology in China published an article titled "Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA" in the journal Nat Commun. The study prepared mRNA (mUox) loaded with ionizable lipid nanoparticles iLAND, which showed great potential in the treatment of hyperuricemia and the prevention of related diseases.
Here, the researchers demonstrated an atavistic strategy for the treatment of hyperuricemia based on the endogenous expression of Uox in hepatocytes. The researchers encapsulated mRNA expressing Uox (mUox) in ionizable LNPs, which consisted of thermostable ionizable lipid A1-D1-5 (N1,N4-bis(3-(bis(2-hydroxydodecyl)amino)propyl)succinamide)25,26, DOPE (1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine), CHO (cholesterol), and DMG-PEG2000 (1,2-dimyristoyl-rac-glycero-3-methoxy polyethylene glycol-2000) as constitutive lipids. The optimized LNP was called the ionizable lipid-assisted nucleic acid delivery system (iLAND). iLAND encapsulated mUox to form mUox@iLAND, which was used to transfect Hepa1-6 cells to express Uox.
Figure 1. Physicochemical characterization of mUox@iLAND and cellular entry. (Zhang M, et al., 2024)
The researchers injected mUox@iLAND intravenously into HU mice and observed its biodistribution, Uox expression, and anti-HU effects. The results showed that mUox@iLAND effectively accumulated in the liver after administration and remained there for a long time, effectively reducing UA levels. Finally, the researchers demonstrated the therapeutic potential of mUox@iLAND in two different HU mouse models. One of them was a persistent mouse model developed in-house, and the results showed that mUox@iLAND successfully delivered mUox to the liver, reduced high levels of SUA, and increased allantoin levels.
Therefore, this study achieved an effective formulation that can potentially be used to establish mRNA-based protein or enzyme expression therapies. The results show that iLAND has established an effective platform for mRNA delivery, and mUox@iLAND has prospective therapeutic potential for treating hyperuricemia and preventing related diseases.
Reference
Zhang M, et al. Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA. Nature Communications, 2024, 15(1): 6463.