#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

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

De novo variants may seem like an uncommon cause for disease as they are genetic alterations that occur sporadically and are not passed down from family members; however, up to 40% of neurodevelopmental disorders (NDDs) are a result of de novo variants. In the context of KAND, some variants are dominantly or recessively inherited, but the majority are de novo. Because these de novo variants are not inherited from parents, they can be hard to detect, which can leave many patients with genetic diseases undiagnosed or misdiagnosed. To address these discrepancies, genetic testing is conducted to analyze patients’ genomes in order to determine disease-causing variants. 

In this study, researchers aimed to highlight the benefits of parent-offspring trio exome sequencing, which is a genetic test used to determine disease-causing changes by analyzing the sequences of genomes belonging to patients and their parents. Of the 231 patients with NDDs that underwent trio exome sequencing, 115 individuals had their disease-causing variants identified, leading to a diagnostic yield of 49.8%. Additionally, researchers observed that 93/115 (80.9%) had de novo variants that were associated with their NDDs. Within the 93 patients with de novo variants, one of them had a de novo KIF1A variant (Arg254Trp). From these findings, scientists demonstrate the prominence of de novo variants in genetic diseases and further emphasize the powerful insight that trio exome sequencing provides in determining these disease-causing changes. With the high potential this form of genetic testing provides, patients with unsolved cases or in need of a diagnosis can tremendously benefit from these advances. For many NDDs like KAND, the only way to arrive at a diagnosis is through genetic testing, such as exome sequencing. With accessibility to these forms of genetic testing being a barrier, there is a high likelihood that there are many others living with KAND undiagnosed. Therefore, making genetic testing more readily available to rare disease communities is extremely important and should be prioritized! If you want to read more about this study, click on the link below!

Rare Disease News

Ionis initiates pivotal clinical study of novel antisense medicine to treat patients with Alexander disease

Ionis, one of the biotech companies that is working to develop therapeutics for KAND, announced a new clinical study of a novel antisense medicine for patients affected by Alexander Disease! This rare and fatal neurological disorder affects children at early onset and is associated with progressive deterioration. The severe disability and loss of independence these patients experience are a result of a mutation that causes the overproduction and toxic accumulation of glial fibrillary acidic protein (GFAP) in the brain. This then disrupts the insulation that protects nerve fibers and supports signal conduction across neurons, leading to neurodegeneration. 

In order to address these health concerns for this fatal disease, Ionis has initiated a pivotal investigational gene therapy study of ION373 in Alexander Disease patients in hopes of targeting the root cause and providing a form of therapeutic treatment. ION373, a drug that is wholly owned by Ionis, is an antisense medicine developed to reduce GFAP levels and reverse the toxic protein accumulation that occurs in the brains of patients with Alexander Disease. Antisense therapy works through the creation of small single-stranded fragments that are used to silence genes of interest by marking the gene for degradation, which in this case would be GFAP. Altogether, these efforts are aimed at developing and commercializing rare disease medicines as a whole and bringing transformative therapies and treatments to patients diagnosed with Alexander Disease. This important initiative led by Ionis demonstrates the forward progression of bringing novel disease modifying therapy to the market for the rare disease community. Interested in knowing more about Ionis’ pivotal study and antisense therapy? Check out the article and video below!

Genethon announces First Patient dosed in Clinical Trial of Investigational Gene Therapy GNT 0004 for Duchenne Muscular Dystrophy

Exciting news! The first dose of a gene therapy trial for Duchenne muscular dystrophy (DMD), GNT 0004, was given to a young boy diagnosed with DMD at I-Motion, the pediatric clinical trial platform in Paris that focuses on neuromuscular diseases! Sponsored by Genethon, this clinical trial represents 30 years of culminated research that is aimed to provide effective treatment for genetic diseases like DMD that have medically unmet needs. DMD is a rare progressive disorder that affects 1 in 3,500 boys and is associated with muscle complications due to the absence of a critical protein, dystrophin, necessary for muscles to function. As dystrophin is one of the largest genes in our genome, a big obstacle was the inability to insert this massive gene into viral vectors for gene therapy. However with GNT 0004, a shortened version of the dystrophin gene is used to fit into viral vectors that are designed to be expressed in muscle tissues. Not only is this a milestone for Genethon, but also an accomplishment for the gene therapy field and rare diseases communities, especially those affected by large genes that exceed the payload of current AAV technology. To read more about the initiation of this clinical trial, check out the article below!

Neural plasticity depends on this long noncoding RNA’s journey from nucleus to synapse

When thinking about rare neurological diseases, the idea of neural plasticity, or the capacity for the nervous system to change through growth and reorganization, is very important to consider especially when thinking about therapeutics aimed at global and shared targets. Neural plasticity plays a major role in learning and memory, as the brain develops new connections among neurons over time to adapt to the surrounding environment. In most neurological disorders, these processes are affected, so having a better understanding of the underlying mechanism associated with neural plasticity can help efforts aimed to repair and enhance this capacity. 

In this article, researchers identified that ADEPTR, a signaling molecule that takes the form of a long, noncoding RNA (lncRNA), plays a major role in activating proteins associated with neural plasticity once neurons are stimulated. LncRNAs continue to be a mystery to many scientists as their functions in the cell are not yet known. What we do know is they are a type of RNA that exceeds 200 nucleotides that do not get turned into proteins. Additionally, they have been observed to be in the nucleus to help regulate the transcription of genes. What researchers found surprising about ADEPTR is its movement from the nucleus to the synapse, which is facilitated by kinesin motors. As a reminder, synapses are areas in between individual neurons that are used for signaling and communication, which is critical for the process of neural plasticity. Additionally, further data from this study show that ADEPTR interacts with proteins that are involved in the structural organization of synapses and that the silencing of ADEPTR resulted in the failure of new synapses forming during stimulation. Overall, these findings provide novel insight regarding the functions of lncRNAs and the process of neural plasticity. To learn more about this research and lncRNA, check out the article and video below!

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