Researchers at Penn Engineering have devised an innovative approach for the synthesis of a vital component of lipid nanoparticles (LNPs), drawing inspiration from space shuttle technology. LNPs play a crucial role in the administration of mRNA therapeutics, as exemplified by the Pfizer-BioNTech and Moderna COVID-19 vaccines. They enhance the ease of LNP manufacturing and enhance their efficacy in facilitating the transportation of mRNA into cells for medical interventions.

In an article published in Nature Communications, Michael J. Mitchell, an Associate Professor in the Department of Bioengineering, presents a novel approach for the synthesis of ionizable lipidoids. These lipidoids are crucial chemical constituents of lipid nanoparticles (LNPs) that play a crucial role in safeguarding and delivering therapeutic payloads. In this study, Mitchell et al. conducted an investigation of the efficacy of mRNA drug delivery for the treatment of obesity as well as the potential of gene-editing techniques for the management of hereditary disorders.

Optimizing the Production Process
Prior research has demonstrated that lipidoids possessing branching tails exhibit superior efficacy in delivering mRNA to cells. However, the processes involved in synthesizing these molecules are both time-consuming and expensive. According to Xuexiang Han, a postdoctoral student in the Mitchell Lab and co-first author of the research, we present an innovative approach for the effective and economical production of these lipidoids.

The procedure entails the amalgamation of three chemical compounds, namely an amine “head,” two alkyl epoxide “tails,” and two acyl chloride “branched tails.” The observed similarity between the fully developed lipidoid and a space shuttle affixed to two booster rockets is not a mere coincidence. Han, a college student, recounts that a documentary on the space shuttle left a lasting impression on him due to the remarkable design of the solid rocket boosters that facilitated the shuttle’s entry into orbit. According to Han, it was determined that the addition of two branch tails as “boosters” to the lipidoid might enhance the transportation of mRNA.

The addition of branching tails greatly improved the ability of LNPs containing the new lipidoid to deliver mRNA to specific cells, similar to how boosters help a rocket get into the atmosphere. “We saw a big increase in the production of a hormone that controls metabolism in certain cells after these lipidoids were used to deliver mRNA.” This development is highly promising, particularly in the context of obesity treatment,” states Mitchell.

The article titled “In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors,” authored by Xuexiang Han, Junchao Xu, Ying Xu, Mohamad-Gabriel Alameh, Lulu Xue, Ningqiang Gong, Rakan El-Mayta, Rohan Palanki, Claude C. Warzecha, Gan Zhao, Andrew E. Vaughan, James M. Wilson, Drew Weissman, and Michael J. Mitchell, was published in Nature Communications on February 26, 2024.
The provided DOI, 10.1038/s41467-024-45537-z,

The research was carried out at the University of Pennsylvania School of Engineering and Applied Science and received funding from the National Institutes of Health (Award DP2 TR002776), the Burroughs Wellcome Fund Career Award at the Scientific Interface, the National Science Foundation CAREER Award (CBET-2145491), and the American Cancer Society (Grant RSG-22-122-01-ET).

Researchers are exploring a new process that has the potential to transform fertility treatment by transferring DNA from skin cells into a donor egg. In the future, this technology could allow women without viable eggs and men in same-sex relationships to have children who are genetically linked to them, although it is not yet ready for clinical usage.

Egg cells that are damaged or deteriorated due to disease, medical procedures, or aging frequently lead to infertility. This treatment involves exchanging the nucleus of a donor egg with the nucleus of a skin cell from the parent to address the issue. After the process, you get an operational egg that only contains genetic material from the intended parent and not from the donor.

The process is known as somatic cell nuclear transfer, and despite its name, it is complex and intricate.

There is a precedent from almost 20 years ago, when the first-ever cloning of an animal, Dolly the sheep, generated interest in adapting this method to people.

Dolly was produced using genetic material from a lone adult sheep. The experts from Oregon Health & Science University (OHSU) explained the novel procedure, which enables the creation of embryos with DNA from both parents.

We are specifically excluding the topic of human cloning.

In January 2022, the researchers initially confirmed the feasibility of their experimental approach. The recent study has advanced this by showing how to attain an accurate chromosome count in the egg cell from the start.

Human sex cells, known as gametes, are haploid, containing half the number of chromosomes compared to other cells in the body. When a haploid egg cell and a haploid sperm cell fertilize one another, the resulting embryo becomes diploid and has a full complement of chromosomes.

OHSU’s team extracted egg cells from mice and removed their nuclei, then substituted them with nuclei from mouse skin cells. “But wait!” you exclaimed. Are skin cells diploid? They are indeed, but the team has a clever answer. They can prompt the implanted nucleus to release half of its chromosomes, creating a haploid cell that closely resembles a normal egg cell.

The eggs can undergo in vitro fertilization (IVF) with sperm, a common process utilized in fertility clinics worldwide. When successful, it leads to the creation of an embryo with chromosomes from both parents.

The approach has an advantage in the rapid production of eggs. Alternative approaches now being studied involve converting skin cells into induced pluripotent stem cells and then guiding these cells to develop into eggs or sperm.

Dr. Paula Amato, the study author, clarified that they are bypassing the process of cell reprogramming. Our technique’s advantage lies in its ability to circumvent the lengthy culture time required for cell reprogramming. Over the course of several months, numerous detrimental genetic and epigenetic alterations might occur.

The ultimate goal, as outlined by senior author Dr. Shoukhrat Mitalipov, is to create eggs for those who do not possess their own, but achieving this objective is still some years in the future. Aleksei Mikhalchenko, the primary author, emphasized the importance of doing a comprehensive assessment of safety, efficacy, and ethical considerations before considering the technique for clinical application.

The Supreme Court of Alabama’s declaration that embryos should be considered as children has brought IVF back into the public spotlight, with many predicting it would be a significant topic in the upcoming US presidential election. The implications of advancements in assisted reproduction will have a global impact, as approximately 1 in 6 people globally are impacted by infertility.

Using a donor egg without integrating DNA from the donor would be a significant and innovative development in reproductive treatment. This work has advanced science’s comprehension of how this concept could perhaps be realized in the future.

The research is featured in Science Advances.

Alzheimer’s disease is a significant health concern for humanity currently. In recent years, there has been significant progress in the creation of highly promising medicinal treatments, along with the testing of revolutionary medicines and diagnostic methods. Debates persist over the true etiology of the disease. A novel proposal proposes that a complex interaction between two proteins may reveal a “mechanical basis” for Alzheimer’s disease.

The paper has recently been published as a preprint and has not yet been subjected to external peer review. The authors from around the world explained the experiments that were used to come up with a six-part theory about how the protein talin interacts with the Alzheimer’s protein amyloid precursor protein (APP) and how it might play a part in the development of the disease. They also discussed the possibility of targeting this system with drugs.

We spoke to Dr. Ben Goult, a senior author and Professor of Mechanistic Cell Biology at the University of Liverpool, regarding the new research.

Goult has a longstanding relationship with the talin protein. In 2021, he proposed a new theory dubbed the MeshCODE theory to explain how memories could be preserved in the brain. The hypothesis proposes that memories could be physically encoded using a talin molecule’s capacity to transition between two stable configurations, similar to how a mechanical computer utilizes binary switches, with each talin shape representing either “0” or “1.”.

Goult and the team have conducted a number of experiments suggesting that talin may not only be responsible for encoding memories in the brain but also be involved in their deterioration in Alzheimer’s disease.

“The significant milestones included demonstrating experimentally the binding of talin to APP and creating a scaled model of APP,” Goult explained to IFLScience. “This video we created accurately depicts full-length proteins to scale, allowing viewers to easily understand the processes.”

Goult promptly reached out to Dr. Julien Chapuis at the Institut Pasteur de Lille, France, with the obtained results. Chapuis’ team had been methodically evaluating various proteins’ impacts on APP. Talin was omitted from their published findings since it did not meet their established criteria.

“Talin has a significant impact on APP processing compared to other proteins when analyzing the data.” Goult informed IFLScience.

Upon integrating our research on talin as a memory molecule with MeshCODE, I recognized a coherent connection, prompting me to commence writing this new study. As everything began to align, it was quite remarkable. Observing the genetic and molecular data coming together was exhilarating over the final months of writing this.

The scientists propose that APP proteins may form a mesh structure that physically links the two sides of a synapse, the space between two neurons where nerve signals travel. Accurate processing of amyloid precursor protein (APP) is crucial for preserving the synchronization of the synapse. However, errors in this process might result in the development of Alzheimer’s disease by disrupting the binary code, known as the MeshCODE, composed of talin “1s” and “0s,” as discussed above. Alzheimer’s disease progresses through the brain when this failure extends throughout brain networks.

This study offers a novel perspective on the potential role of APP in normal neuronal activity. Goult explained to IFLScience that errors in mechanical homeostasis can lead to issues.

The explanation fits with what we are learning about the pathology of Alzheimer’s, especially the presence of misfolded amyloid-β protein plaques in the brains of people with the disease, which are caused by improper processing of APP.

“It also suggests several potential new approaches to treating Alzheimer’s or detecting it sooner,” Goult remarked.

This is all still theoretical. Goult and colleagues propose that the next phase should involve thorough experimental confirmation and improvement of these theories, which they are now doing in the laboratory and plan to progress to animal research soon.

This aligns with the pivotal sixth aspect of the theory, suggesting the potential repurposing of current medications to mitigate the progression of Alzheimer’s disease.

Focal adhesions (FAs) are substantial protein structures that link cellular components to their external surroundings. Previous genetic studies indicate a connection between the stability of fatty acids (FAs) and the stability of amyloid precursor protein (APP) at the synapse. We already possess medicines that are recognized for their ability to stabilize FAs, commonly employed in cancer therapy. Could these possibly exert a similar impact on amyloid precursor protein (APP) in the brain by restoring the APP’s mechanical structure and inhibiting the degradation that results in Alzheimer’s disease?

Goult and colleagues are eager to further examine this intriguing idea.

Goult’s experience with talin has been full of shocks, and this bold new idea is the latest addition to that list.

Goult expressed enthusiasm for studying individual proteins and their functions, appearance, and interactions, which can generate innovative concepts that span from molecular complexes to synapses, neurons, and the entire brain.

Hopefully, these new data and the resulting theories can expedite the development of novel treatments for this condition.

The preprint is accessible on bioRxiv but has not been reviewed by external peers yet.