Lipid nanoparticle delivery of mRNA gene therapy for hemophilia A

The Problem

Hemophilia is a rare genetic condition affecting more than 250,000 people worldwide, according to a 2021 report from the World Federation of Hemophilia [1]. People with the disease lack the ability to produce a blood clotting factor, which is factor VIII for hemophilia A [2]. The current standard of care is factor replacement therapy which requires multiple intravenous injections per week, often starting a young age. This represents a huge burden on patients’ quality of life and creates treatment compliance issues [2]. Gene therapies using single stranded DNA and adeno associated viruses (AAVs) as the delivery vehicle have emerged as a way to stimulate endogenous production of the missing clotting factor [2], [3] Such therapies drastically decrease the treatment frequency [3], [4]. However, durability of treatment remains an issue, especially in hemophilia A due to difficulties in effectively packaging the larger factor VIII coding sequence into AAVs. Manufacturing AAV-based therapies is also cumbersome and difficult to achieve on a large scale while maintaining appropriate quality [3]. Finally, there is a risk of oncogenic mutagenesis associated with viral integration [5], [6].

The Solution

Nanoheme proposes to design optimized lipid nanoparticles (LNPs) for the delivery of a mRNA gene therapy for hemophilia A. Significant advancements were made in mRNA vaccines delivered via LNPs around the year 2020 as part of the global effort to develop a vaccine for COVID-19. The same technology shows promise to treat many cancers and rare diseases [7], such as hemophilia [5], [6]. There is no risk of oncogenic mutagenesis when using mRNA-loaded LNPs for hemophilia, and no promoter is needed, which decreases the delivery vehicle volume required [5], [6]. The aim of this project is to synthesize and characterize LNPs with adequate packaging capacity for a codon-optimized mRNA sequence corresponding to factor VIII, and that bind specifically to liver sinusoidal endothelial cells (LSECs), where factor VIII is produced naturally in non-carriers of the disease. 

Recruitment

Recruitment 2023 is closed for research members.

References

[1] World Federation of Hemophilia, “Annual Global Survey 2021,” WFH, Oct. 2022. [Online]. Available: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www1.wfh.org/publications/files/pdf-2324.pdf

[2] D. Okaygoun, D. D. Oliveira, S. Soman, and R. Williams, “Advances in the management of haemophilia: emerging treatments and their mechanisms,” J. Biomed. Sci., vol. 28, no. 1, p. 64, Dec. 2021, doi: 10.1186/s12929-021-00760-4.

[3] A. C. Nathwani, A. M. Davidoff, and E. G. D. Tuddenham, “Advances in Gene Therapy for Hemophilia,” Hum. Gene Ther., vol. 28, no. 11, pp. 1004–1012, Nov. 2017, doi: 10.1089/hum.2017.167.

[4] J. P. Cunha, “Roctavian (Valoctocogene Roxaparvovec-Rvox Suspension) Drug.” RxList, Jul. 19, 2023. [Online]. Available: https://www.rxlist.com/roctavian-drug.htm

[5] C.-Y. Chen et al., “Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles,” Mol. Ther. - Nucleic Acids, vol. 20, pp. 534–544, Jun. 2020, doi: 10.1016/j.omtn.2020.03.015.

[6] J. Russick et al., “Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA,” Haematologica, vol. 105, no. 4, pp. 1129–1137, Apr. 2020, doi: 10.3324/haematol.2018.210583.

[7] “Harnessing the potential of mRNA to overcome major healthcare challenges,” Sanofi, Jul. 24, 2023. https://www.sanofi.com/en/magazine/our-science/harnessing-the-potential-of-mrna-to-overcome-major-healthcare-challenges

Team Leads