Leigh Disease

SEOUL, South Korea, Feb. 23, 2024 /PRNewswire/ -- Gene editing technology could revolutionize the treatment of genetic diseases, including those that affect the mitochondria—cell structures that generate the energy required for the proper functioning of living cells in all individuals. Abnormalities in the mitochondrial DNA (mtDNA) could lead to mitochondrial genetic diseases. Continue Reading Scientists improved adenine base editing in mitochondrial DNA using engineered transcription activator-like effector-linked deaminases (TALEDs). The engineered TALEDs minimize off-target gene edits, offering the potential to treat mitochondrial genetic disorders affecting thousands worldwide. Targeted base editing of mammalian mtDNA is a powerful technology for modeling mitochondrial genetic diseases and developing potential therapies. Programmable deaminases, which consist of a custom DNA-binding protein and a nucleobase deaminase, enable precise mtDNA editing. There are two types of programmable deaminases for genome editing: cytosine base editors and adenine base editors, such as DddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs). These editors bind to specific DNA sites in the mitochondrial genome and convert bases, resulting in targeted cytosine-to-thymine (C-to-T) or adenine-to-guanine (A-to-G) conversions during DNA replication or repair. However, the current gene editing approaches have many limitations, including thousands of off-target A-to-G edits while using TALEDs. Researchers from Korea University engineered TALEDs for improved A-to-G precision editing. Notably, in this breakthrough study conducted by Associate Professor Hyunji Lee and his collaborators, researchers succeeded in developing the world's first animal model with A-to-G mtDNA edits achieved using engineered TALEDs. Their study was published in Volume 187, Issue 1, of the journal Cell on January 4, 2024. To overcome the limitation of unintended RNA edits, the researchers modified the substrate-binding site in TadA8e—the deoxy-adenine deaminase region in TALEDs—and developed TALED variants with fine-tuned deaminase activity. When asked to comment on the engineered TALEDs, Assoc. Prof. Lee remarks, "To address limitations of the conventionally used TALEDs, we created and assessed 209 TALED variants. Each variant replaced one of the 11 amino acid residues near the substrate-binding pocket in the protein of interest with one of the other 19 amino acid residues." The results of the study showed that the engineered TALEDs significantly decreased off-target RNA edits by over 99%. The engineered TALEDs also minimized off-target mutations in mtDNA and bystander edits—unintended changes that occur at locations in the genome near the targeted site during editing processes—at a specific target site. In contrast to the original TALEDs, these engineered TALEDs did not exhibit toxicity. They also did not lead to developmental arrest in mouse embryos. Researchers generated mice carrying pathogenic mtDNA mutations associated with Leigh syndrome—a mitochondrial genetic disease. The generated mice displayed reduced heart rates, which is an expected disease outcome. The ability to edit mtDNA with improved precision opens avenues for studying and treating other mitochondrial genetic disorders. The research aligns with the broader trend of personalized medicine, offering hope for individuals with specific mitochondrial genetic variations. Prof. Lee's research hints at a potential future in which the mitochondrial gene editing technology gains similar recognition. With mitochondrial genetic diseases affecting approximately one in 5,000 people globally, this technology could bring transformative treatments in the next five to ten years. The achievement of correcting mitochondrial A-to-G in mice not only highlights the efficacy of the novel gene editing method but also signals a significant step toward developing approved treatments for mitochondrial genetic diseases. The impact of this research extends beyond the laboratory, holding promise for real-world applications that could revolutionize healthcare and improve the lives of those affected by mitochondrial disorders. Reference Title of original paper: Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA Journal: Cell DOI: About Korea University College of Medicine Website: Contact: Soo-Jin Jeon +82 2 3407 4040 373376@email4pr.com SOURCE Korea University College of Medicine

Feb. 15, 2024 -- Taysha Gene Therapies, Inc. (Nasdaq: TSHA) (“Taysha” or “the Company”), a clinical-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS), today provided an update on its deprioritized pipeline programs as part of an ongoing effort to help support their further potential development. Taysha has been working to find ways to advance its deprioritized programs. On November 13, 2023, Taysha terminated its existing loan and security agreement and entered into a new loan and security agreement that provides consent to allow the Company to transfer intellectual property (IP) for several deprioritized programs to third parties in a more efficient manner. The Company’s new loan and security agreement also extended its cash runway into 2026. TSHA-120: The Company initiated the transfer of the United States Food and Drug Administration Investigational New Drug (IND) application and investigational clinical trial material for TSHA-120 in giant axonal neuropathy (GAN) to clinical trial collaborator National Institute of Neurological Disorders and Stroke (NINDS), creating an opportunity for continued clinical evaluation of TSHA-120 in GAN. Additionally, the Company entered discussions with the originating advocacy organization regarding TSHA-120 in an effort to transfer rights back to the advocacy organization to move the program forward. TSHA-101: The Company transferred rights back to Queen’s University (Queen’s) for TSHA-101 in GM2 gangliosidosis, resulting in Queen’s regaining exclusive IP to the program. TSHA-104 and TSHA-112: The Company transferred rights back to the originating institution for select programs, including TSHA-104 in SURF1-associated Leigh syndrome and TSHA-112 in APBD. TSHA-118: The Company provided investigational clinical trial material for TSHA-118 in CLN1 to support an individual-patient investigator-initiated IND request from RUSH University Medical Center for the treatment of a patient with CLN1 disease. “Today’s announcement demonstrates meaningful progress to advance important development work for several deprioritized programs. Creating options for these programs has been a focus since the Company completed a management change in December 2022, and the new loan and security agreement afforded the flexibility to implement certain opportunities,” said Sean P. Nolan, Chairman and Chief Executive Officer of Taysha. “As we continue to focus on advancing our lead TSHA-102 program for the treatment of Rett syndrome, we are pleased that we can ensure these programs are provided to the right advocates, clinicians and scientific experts who can potentially move these programs forward for the benefit of patients.” The Company continues to explore potential partnerships and opportunities for its other deprioritized programs to help support their further potential development. Taysha Gene Therapies (Nasdaq: TSHA) is a clinical-stage biotechnology company focused on advancing adeno-associated virus (AAV)-based gene therapies for severe monogenic diseases of the central nervous system. Its lead clinical program TSHA-102 is in development for Rett syndrome, a rare neurodevelopmental disorder with no approved disease-modifying therapies that address the genetic root cause of the disease. With a singular focus on developing transformative medicines, Taysha aims to address severe unmet medical needs and dramatically improve the lives of patients and their caregivers. The Company’s management team has proven experience in gene therapy development and commercialization. Taysha leverages this experience, its manufacturing process and a clinically and commercially proven AAV9 capsid in an effort to rapidly translate treatments from bench to bedside. For more information, please visit www.tayshagtx.com. The content above comes from the network. if any infringement, please contact us to modify.

Many neurodegenerative diseases, such as dementia, are characterized by the abnormal aggregation of proteins inside cells, and treatments are being developed to break them up. But new research suggests that for some diseases, the aggregates are not directly killing cells. Aggregates prevent a protein, SIFI, from switching off the cells' stress response, and the constant stress kills cells. This suggests a strategy to treat these diseases without needing to mop up protein aggregates. Many neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are characterized by the accumulation of protein clumps, or aggregates, in the brain, which has led scientists to assume that the protein tangles kill brain cells. The search for treatments that break up and remove these tangled proteins has had little success, however. But a new discovery by University of California, Berkeley, researchers suggests that the accumulation of aggregated proteins isn't what kills brain cells. Rather, it's the body's failure to turn off these cells' stress response. In a study published online Jan. 31 in the journal Nature, the researchers reported that delivering a drug that forces the stress response to shut down saves cells that mimic a type of neurodegenerative disease known as early-onset dementia. According to lead researcher Michael Rapé, the finding could offer clinicians another option for treatment for some neurodegenerative diseases, at least for those caused by mutations in the protein that switches off the cellular stress response. These include inherited diseases that lead to ataxia, or loss of muscle control, and early-onset dementia. In addition, Rapé noted that other neurodegenerative diseases, including Mohr-Tranebjærg syndrome, childhood ataxia and Leigh syndrome, are also characterized by stress responses in overdrive and have symptoms similar to those of the early onset dementia mimicked in the new study. "We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet, we now found that aggregates prevent silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that's what kills the cells," said Rapé, head of the new division of molecular therapeutics in UC Berkeley's Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator. "We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer's disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases." Key to the discoveries by Rapé's lab was the researchers' finding that stress responses need to be turned off once a brain cell has successfully addressed a difficult situation. Rapé explained this finding to his son in simple terms: You not only need to clean up your room, but also turn out the light before going to bed. If you don't turn off the light, you can't fall asleep, but if you turn it off before you cleaned up your room, you would stumble if you had to get up in the dark. Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn't turn off the stress response, the cell will ultimately die. "Aggregates don't kill cells directly. They kill cells because they keep the light on," he said. "But that means that you can treat these diseases, or at least the dozen or so neurodegenerative diseases that we found have kept their stress responses on. You treat them with an inhibitor that turns off the light. You don't have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable." In their paper, Rapé and his colleagues describe a very large protein complex they discovered and called SIFI (SIlencing Factor of the Integrated stress response). This machine serves two purposes: It cleans up aggregates and, afterward, turns off the stress response triggered by the aggregated proteins. The stress response controlled by SIFI is switched on to deal with specific intracellular problems -- the abnormal accumulation of proteins that end up at the wrong location in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response signaling that kills the cells. "The SIFI complex would normally clear out the aggregating proteins. When there are aggregates around, SIFI is diverted from the stress response, and the signaling continues. When aggregates have been cleared -- the room has been cleaned up before bedtime -- then the SIFI is not diverted away anymore, and it can turn off the stress response," he said. "Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it. And so that's why silencing never happens when you have aggregates, and that's why cells die." A future treatment, Rapé said, would likely involve administration of a drug to turn off the stress response and a drug to keep SIFI turned on to clean up the aggregate mess. Ubiquitin Rapé, who is also the Dr. K. Peter Hirth Chair of Cancer Biology, studies the role of ubiquitin -- a ubiquitous protein in the body that targets proteins for degradation -- in regulating normal and disease processes in humans. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal that was required for the elimination of proteins that tend to aggregate inside cells. Only later did other researchers find that mutations in UBR4 are found in some inherited types of neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases. "This was a unique opportunity: We had an enzyme that makes an anti-aggregation signal, and when it's mutated, it causes aggregation disease," he said. "You put these two things together and you can say, 'If you figure out how this UBR4 allows sustained cell survival, that probably tells you how aggregates kill cells.'" They found that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and they found that this SIFI machinery was needed when a cell couldn't sort proteins into its mitochondria. Such proteins that end up at the wrong location in cells tend to clump and, in turn, cause neurodegeneration. "Surprisingly, though, we found that the core substrates of the SIFI complex were two proteins, one of which senses when proteins don't make it into mitochondria. That protein detects that something is wrong, and it then activates a kinase that shuts down most of new protein synthesis as part of a stress response, giving the cell time to correct its problem with bringing proteins to the right location," he said. This kinase is also degraded through SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case a protein, to regulate important activities in the cell. By helping degrade these two proteins, the SIFI complex turns off the stress response that is caused by clumpy proteins accumulating at the wrong location. "That's the very first time that we've seen a stress response turned off in an active manner by an enzyme -- SIFI -- that happens to be mutated in neurodegeneration," Rapé said. While investigating how SIFI can turn off the stress response at the right time -- only after the room had been cleaned up -- the researchers found that SIFI recognizes a short protein segment that acts as a kind of ZIP code that allows proteins or protein precursors to get into the mitochondria, where they are processed. When they are prevented from getting in, they accumulate in the cytoplasm, but SIFI homes in on that ZIP code to eliminate them. The ZIP code looks just like the light switch. "When you have aggregates accumulating in the cytoplasm, now the ZIP code is still in the cytoplasm, and there's a lot of it there," he said. "And it's the same signal as you would have in the proteins that you want to turn off. So it basically diverts the SIFI complex from the light switch back to the mess. SIFI tries to clean up the mess first, and it cannot turn off the light. And so when you have an aggregate in the cell, the light is always on. And if the light is always on, if stress signaling is always on, the cell will die. And that's a problem." Rapé suspects that many intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and may prevent the cell from switching off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases. Already, another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has been shown to improve memory in mice and reduce age-related cognitive decline. "That means there is the prospect that by manipulating stress silencing, by turning off the light with chemicals, you might target other neurodegenerative diseases, as well," he said. "At the very least, it's another way we could help patients with these diseases. In the best possible way, I think it will change how we treat neurodegenerative diseases. That's why this is a really important story, why I think it's very exciting." Rapé, already a co-founder of two startups, Nurix Therapeutics Inc., and Lyterian Therapeutics, is now looking to develop therapies to silence the stress response while maintaining the cell's cleanup of protein aggregates. Co-authors with Rapé are postdoctoral fellows Diane Haakonsen, Michael Heider and Samuel Witus and graduate student Andrew Ingersoll, all of UC Berkeley, and Kayla Vodehnal, Takeshi Uenaka and Marius Wernig of Stanford. The work was supported primarily by the Stinehart-Reed Foundation and the National Institutes of Health (RF1 AG048131, T32MH020016-25).