Be a part of the puzzle in the ever-evolving therapeutic world with GALLS – a 5,000-piece jigsaw that’s connecting the regulatory edges. As you put the pieces together, you’ll uncover exciting new research that could make a world of difference.
In 2022, researchers from University College London and the NIH made a groundbreaking discovery, uncovering the association between the gene-encoding protein UNC13A and the TDP-43 protein, long believed to be linked to ALS pathology. This discovery has led to further research on two potential therapeutic targets: PIKFYVE and SYF2, which could revolutionize treatments for the condition.
ALS is a devastating neurodegenerative disease that threatens the lives of its victims, often taking them within 2-5 years of diagnosis. With both sporadic and genetic forms, ALS is a complex condition that has no known cure. The outcome is uniformly fatal, making it a challenging and heartbreaking diagnosis for those affected.
In February, two groundbreaking studies were published in Cell and Cell Stem Cell, showing the potential of PIKFYVE inhibition and SYF2 suppression in treating a variety of diseases. These studies offer new hope for those affected by these conditions and could revolutionize the way we approach treatment in the future.
Dr. Justin Ichida, a renowned stem cell scientist at USC, has achieved a groundbreaking feat: He has successfully led two studies that have the potential to revolutionize stem cell research. His innovative work is already gaining recognition and admiration in the scientific community.
PIKFYVE: An Underappreciated Mechanism
In 2016, scientists made a groundbreaking discovery linking the protein PIKFYVE to ALS, which was later published in Nature Medicine in 2018. This groundbreaking discovery opened the door to a new understanding of the role of this protein in ALS and could potentially lead to new treatments.
The recently published study by Ichida has shed light on the workings of PIKFYVE and has revealed that this mechanism is applicable to a wide range of ALS models. This groundbreaking research provides a much-needed insight into how this debilitating disease works and could lead to potential treatments in the future.
TDP-43 is a vital protein found in the nucleus of healthy cells, but in Amyotrophic Lateral Sclerosis (ALS) it is lost, resulting in toxic clumps that can cause devastating damage.
Ichida et al. made a groundbreaking discovery in their paper published on Feb. 7; they found that inhibition of PIKFYVE kinase activates a unique protein clearance process, in which aggregation-prone proteins are exocytosed from the cell. This finding sheds light on a novel approach to protein clearance and could have implications for many areas of research.
Two pioneering companies are working towards a greater understanding of their role in the clinic. AcuraStem, based in California, is leading the charge in this effort. With their cutting-edge technologies and innovative approaches, they are paving the way for a more comprehensive understanding of healthcare.
AcuraStem was founded in 2016 by an inspiring group of innovators, including Ichida, Drs. Paul August and Qing Liu, and CEO Sam Alworth. Their lead asset is targeting PIKFYVE, a revolutionary step in the world of medical technology. With their vision and expertise, AcuraStem is poised to make a major impact in the field.
According to our research, we have uncovered an overlooked way of keeping neuronal proteins in balance, which can help neurons clear away toxic protein clusters. Through our findings, we hope to revolutionize how we approach the regulation of proteostasis in neurons.
In a strategic shift, AcuraStem is prioritizing the development of an antisense oligonucleotide (ASO) to target PIKFYVE, rather than the small molecule initially intended. This new approach promises to be more effective in achieving the desired results.
In a head-to-head test in vivo, the results showed that ASOs are far more effective than small molecules in inhibiting PIKFIVE. While small molecules provide transient inhibition, ASOs can suppress PIKFIVE for an entire month. This remarkable difference in effectiveness proves ASOs to be a powerful tool in the fight against disease.
Restoring Endolysosomal Function
Verge Genomics, a Bay Area-based company, is developing a breakthrough clinical-stage program that could revolutionize the treatment of PIKFYVE. This cutting-edge program has the potential to drastically improve the lives of millions of people living with this debilitating condition.
Alice Zhang, CEO and co-founder of Verge, made a groundbreaking contribution to the 2018 Nature Medicine paper by leveraging the power of Verge’s machine learning-based ConVERGE platform to discover PIKFYVE as a therapeutic target for ALS. This revolutionary discovery has the potential to revolutionize the treatment of this devastating condition.
BioSpace recently had the opportunity to speak with Robert Scannevin, Ph.D., the Chief Scientific Officer at the company, regarding the exciting discovery that sparked their new program. Dr. Scannevin discussed the implications of this breakthrough and what it means for the future.
Through our research, we uncovered a network of dysregulated biology that can be linked to multiple ALS driver genes, providing valuable insight into the causes of this devastating condition. Our findings could be the key to unlocking new treatments and therapies for ALS in the future.
PIKFYVE emerged as the clear frontrunner in the search for the best target. Its impressive performance and high ranking made it the undeniable choice.
We’ve uncovered an essential link between the genetic drivers of ALS and a crucial cellular pathway known as intracellular trafficking within the endolysosomal system. This dysfunction appears to be a common cause of the disease, making it a promising target for future treatments.
Negative effects on intracellular trafficking can have devastating consequences, leading to nerve degeneration and disrupting a multitude of downstream events.
PIKFYVE is on a mission to bring balance back to endolysosomal function – a key component of cell health and well-being. With their groundbreaking research and innovative solutions, they are working to revolutionize how we understand and effectively manage this vital aspect of our cellular systems.
In November 2022, Verge’s groundbreaking new drug, VRG50635, began its Phase I trial with the first healthy volunteer. This small molecule inhibitor of PIKFYVE marks a major milestone in the world of drug development and offers a promising solution for those suffering from related conditions.
Verge’s compound has been demonstrated to be safe and well-tolerated in five single ascending dose cohorts, with excellent pharmacokinetics. Scannevin reported that the compound has been an effective and successful addition to their lineup.
By the end of 2021, the company anticipates beginning studies in ALS patients as part of the trial’s first phase, with completion expected by mid-2023. This represents a significant milestone in their efforts to deliver groundbreaking treatments for this debilitating condition.
With AcuraStem and Verge trials in full swing, the Ichida team is eagerly awaiting the results to see if their treatments are effective in patients. They hope to have an answer soon on whether the treatments have been successful.
The Discovery of SYF2
In a groundbreaking study published on Feb. 2 in Cell Stem Cell, Ichida and Alworth, along with their collaborators, have presented compelling evidence for the existence of SYF2.
In a groundbreaking study, researchers reprogrammed skin and blood samples from ALS patients into motor neurons, then used these to screen an impressive 2,000 FDA-approved compounds for their potential to fight the disease. By doing this, they hope to discover compounds that could be broadly effective against both sporadic and familial ALS.
In their search for a treatment for C9ORF72 ALS, Ichida’s team identified 40 compounds with potent effects. Of these, 11 were androgenic, but due to potential side effects, the team sought to find an alternative target downstream of that androgen signaling to achieve the same therapeutic outcome.
The Broad Institute of Harvard and MIT have developed a revolutionary public bioinformatics database called the Connectivity Map, which has recently identified SYF2 as a key component. This groundbreaking discovery has the potential to revolutionize our understanding of biological systems and open up new possibilities for medical research.
The team made a remarkable discovery – by suppressing the activity of the SYF2 gene-encoded spliceosome-associated factor protein, they were able to rescue motor neuron degeneration and improve motor deficits in mouse models. This promising breakthrough could lead to potential treatments for motor neuron diseases.
Alworth hailed it as a “dark horse, fantastic approach” – a surprise success that has really taken off.
SYF2 and TDP43 have been found to be involved in the same biological pathway, as revealed by Alworth’s research. This pathway focuses on both gain and loss of function, making it an important area of study for understanding the complexities of biological processes.
Dr. Pestana and his team have identified a potential target for ALS therapy that could affect multiple TDP 43 targets. This target, which has been identified as UNC13A and stathmin-2, could potentially provide a breakthrough in the treatment of this devastating disease. With further research, this target could be the key to unlocking a better quality of life for those living with ALS.
AcuraStem is pushing the boundaries of medical research by testing an innovative asset targeting SYF2 in preclinical studies. This cutting-edge research has the potential to revolutionize current treatments, and could lead to groundbreaking advances in medical science.
The company is placing a big bet on UNC13A, a protein that Alworth believes is essential for disease progression. Their confidence in this protein as a potential game-changer is palpable, and could potentially revolutionize the way we view, treat, and prevent many diseases.
UNC13A has been firmly established as a legitimate player in the genetic landscape. But what if we were to turn the tables and look at it from a different angle?
The pieces of the puzzle are slowly coming together in the search for a cure for one of the world’s most daunting diseases. What that cure will be remains a mystery, but it is clear that progress is being made. It is only a matter of time before we unlock the answer to this enduring medical conundrum.