Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery

Madigan, Victoria; Zhang, Yugang; Raghavan, Rumya; Wilkinson, Max E.; Faure, Guilhem; Puccio, Elena; Segel, Michael; Lash, Blake; Macrae, Rhiannon K.; Zhang, Feng

doi:10.1073/pnas.2307812120

Cited by 13 publications

(3 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been noted that PNMA capsids should be suitable as delivery vehicles for therapeutic agents such as RNA vaccine delivery and gene therapy 18,19,32,82 ; such therapies involve bioengineering capsid proteins for the delivery of designer cargo, such as mRNA. The beauty of PNMA1 and PNMA4 is that they would require no engineering to function as therapeutic agents for subfertility because they could naturally harbor pro-fertility cargo.…”

Section: Discussionmentioning

confidence: 99%

“…We reasoned that the conservation of PNMA genes is unlikely to be based on their autoantigenic properties after ectopic expression in neoplasms. While Pnma5 is implicated in mouse oocyte development via an unknown mechanism 17 , little is known about the non-pathological roles of the other genes other than that some seem to have retained the ability to form capsids when expressed in human cells or bacteria 18,19 . The autoantigenicity of PNMA2, in fact, requires capsid formation 20 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

Wood,

Henriques,

Cullen

et al. 2024

Preprint

View full text Add to dashboard Cite

The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

Wood,

Henriques,

Cullen

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Obviously, the probabilities for containing more than one electron are infinitesimally small. For comparison, parameters from a typical cryo‐EM experiment, such as for the FSC shown in Figure 1b (Madigan et al, 2024 ), might involve a total fluence of ~30 e − /Å 2 , fractionated into 24 frames, so in each frame there would be an expectation of ~1.25 electrons/Å 2 . It was stated in Jonaid et al that the frames were then motion‐corrected to compensate for the large translations of the virions over the course of the 20 s movies.…”

mentioning

confidence: 99%

The myth of high‐resolution liquid phase biological electron microscopy

Egelman

2024

Protein Science

View full text Add to dashboard Cite

Cryo‐electron microscopy (cryo‐EM) has transformed structural biology over the past 12 years, with it now being routine rather than exceptional to reach a near‐atomic level of resolution for proteins and macromolecular complexes. Samples are immobilized by vitrification and this sample can be maintained at liquid nitrogen temperatures in the vacuum of the electron microscope with negligible sublimation. Due to the low electron doses needed to avoid radiation damage, averaging over tens of thousands to hundreds of thousands of particle images is used to achieve a high signal‐to‐noise ratio. An alternative approach has been proposed where samples are at room temperature in the liquid state, maintained in the vacuum of the electron microscope by thin film enclosures that are relatively transparent to electrons while preventing evaporation of the liquid. A paper has argued that using this liquid‐phase approach, higher resolution (3.2 Å) can be achieved than using cryo‐EM (3.4 Å) when imaging and reconstructing adeno‐associated virus particles. I show here that these assertions are untrue, and that basic principles in mathematics and physics would need to be violated to achieve the stated resolution in the liquid state. Thus, high resolution liquid phase EM of macromolecules remains science fiction.

show abstract

Gene editing therapy for cardiovascular diseases

Wu,

Yang,

Zhang

et al. 2024

MedComm

View full text Add to dashboard Cite

The development of gene editing tools has been a significant area of research in the life sciences for nearly 30 years. These tools have been widely utilized in disease detection and mechanism research. In the new century, they have shown potential in addressing various scientific challenges and saving lives through gene editing therapies, particularly in combating cardiovascular disease (CVD). The rapid advancement of gene editing therapies has provided optimism for CVD patients. The progress of gene editing therapy for CVDs is a comprehensive reflection of the practical implementation of gene editing technology in both clinical and basic research settings, as well as the steady advancement of research and treatment of CVDs. This article provides an overview of the commonly utilized DNA‐targeted gene editing tools developed thus far, with a specific focus on the application of these tools, particularly the clustered regularly interspaced short palindromic repeat/CRISPR‐associated genes (Cas) (CRISPR/Cas) system, in CVD gene editing therapy. It also delves into the challenges and limitations of current gene editing therapies, while summarizing ongoing research and clinical trials related to CVD. The aim is to facilitate further exploration by relevant researchers by summarizing the successful applications of gene editing tools in the field of CVD.

show abstract

Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery

Cited by 13 publications

References 56 publications

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

The myth of high‐resolution liquid phase biological electron microscopy

Gene editing therapy for cardiovascular diseases

Contact Info

Product

Resources

About