#ScienceSaturday posts share relevant and exciting scientific news with the KAND community. This project is a collaboration between KIF1A.ORG’s Research Engagement Team Leader Alejandro Doval, President Kathryn Atchley, Science Communication Associate Aileen Lam and Chief Science Officer Dr. Dominique Lessard. Send news suggestions to our team at impact@kif1a.org.

Recent KIF1A-Related Research

Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response

This week, we will be talking about a special and complex cellular structure known as mitochondria, a.k.a the powerhouse of the cell! Mitochondria have many functions that include supplying our cells with energy in the form of ATP and producing reactive oxygen species (ROS). ROS are a type of unstable molecule that contain oxygen and can interact with cellular molecules in both beneficial and harmful ways. In this article, we will be discussing the role mitochondria plays in generating ROS from hydrogen peroxide (H2O2), as ROS overproduction and overexposure can lead to neuropathological conditions. However, when produced at normal levels, ROS can help regulate neuronal plasticity, activity, and homeostasis. 

In this article, researchers demonstrate that H2O2 plays a role in the secretion of neuropeptides, which are modulators of behavior, physiology, and cellular environments packaged in dense core vesicles (DCVs). To provide more insight on the regulation of DCV release of neuropeptides, these scientists reported that the H2O2 produced from mitochondria promoted the secretion of neuropeptides to activate a stress response in Caenorhabditis elegans (C. elegans, a.k.a. tiny worms that live in soil and are commonly used as model organisms in research).

C. elegans. Wikimedia Commons

Additionally, they investigated the effects of mutations in UNC-104, the C. elegans version of KIF1A. They found that these mutations significantly reduced neuropeptide secretion, which shows evidence that UNC-104 plays an important role in DCV secretion, as this gene codes for the kinesin-3 motor protein to assist in transport of these neuropeptides. On top of that, changes made to the diet of these organisms also affected the levels of H2O2, which in turn affect the release of neuropeptides to regulate a stress response. Overall, this article details the multifaceted nature of neuronal regulation within our bodies. This concept is important to explore when considering the different molecules and pathways that could lead to neuropathological conditions. Seeing that UNC-104/KIF1A is involved in this process shows us that its function is complex, critical, and very involved throughout the body. To read more about this study, check out the article below! 

Rare Disease News

No AAV? No prob­lem. Code Bio­ther­a­peu­tics joins the search for a non-vi­ral gene ther­a­py

Advancements in gene therapy have been on the rise as a result of the progress achieved in the field of precision medicine. Although many milestones have been made, there are still areas of research that need to be further studied and barriers that need to be overcome. A therapeutic approach that may sound familiar is AAV-directed gene therapy, which aims to deliver and replace DNA in targeted cells. This type of viral vector technology has proven to be revolutionary in introducing a new mechanism for treatment; however, two obstacles that scientists run into are the combative reactions from patients’ immune systems and the limitations in gene size that can be effectively delivered by this AAV system. 

In response to these concerns, a new and emerging company called Code Biotherapeutics is developing a synthetic DNA-based vector, called 3DNA, which includes a series of synthetic DNA strands that are linked together to form a scaffold. Fortunately, this structure does not trigger the immune system, allowing scientists the opportunity to re-dose patients at a low dosage and avoid safety issues that come with giving higher doses. Additionally, this vector is not limited to the size of the gene that scientists want to deliver to patient cells and can expand this type of therapy to diseases that were not able to undergo AAV therapy. Their data show that this type of vector was able to successfully deliver gene constructs up to 10 kb in length! To put it in perspective, KIF1A is currently too large for AAV therapy as its size is around 5 kb. The implications of this new synthetic DNA-based vector are huge and currently therapies for Type 1 Diabetes and Duchenne Muscular Dystrophy are in progress. To read more about this quest to find an effective non-viral gene therapy, check out the article below! If you are curious about what synthetic DNA is, click on the video below as well!

New approach to gene therapy can correct any disease-causing mutation within a gene

On the topic of gene therapy, another popular approach is gene editing via the CRISPR/Cas9 system, which is used to target and correct disease-causing mutations. This novel technique for gene editing opened many doors for therapeutics to address diseases resulting from mutations within the gene. However, the limitations of this approach have to do with the repair strategy that occurs after the DNA is edited by the CRISPR/Cas9 system, which is called homology-directed repair (HDR). This mechanism of repair is used to fix double stranded breaks that occur in the DNA by utilizing a DNA template and specific proteins that are present during cell division. HDR is then limited in its ability to be effective in certain adult tissues since cell division rarely occurs there. Additionally, diseases caused by a single gene can be a result of multiple mutations within that gene, so a HDR approach would make repairing each of these mutations very tedious and costly. Therefore, to address these limitations, Dr. Cavener and his team at Penn State designed a new approach called Co-opting Regulation Bypass Repair (CRBR). 

In this article, this new strategy is highlighted for its ability to be effective in dividing and non-dividing cells and target a variety of mutations within a gene by using a different mechanism called non-homologous end joining (NHEJ). This repair pathway can insert a sequence that contains a condensed version of the normal gene between the mutated gene’s promoter (the “on/off switch” of the gene) to replace the mutated gene. All in all, the CRBR strategy expands the possibilities of gene therapy conducted via the CRISPR/Cas9 mechanism by providing solutions to address the limitations. Want to read more about this new gene editing approach and NHEJ? Click on the article below!

“…Even when a disease is caused by a single gene, it can result from a variety of different mutations within that gene… with homology-directed repair, we’d need to design and test the strategy for each and every one of those mutations, which can be expensive and time-intensive…this [CRBR] approach is especially promising for rare genetic diseases caused by a single gene, where limited time and resources typically preclude design and testing for the many possible disease-causing mutations.”

Dr. Douglass Cavener

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