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Neuroscientists have developed a single-dose genetic medicine that has been proven to halt the progression of both ALS and FTD in mice -- and may even offer the potential to reverse some of the effects of the fatal diseases. It may also hold opportunities for treating more common forms of dementia, such as Alzheimer's disease. Neuroscientists at Macquarie University in Australia have developed a single-dose genetic medicine that has been proven to halt the progression of both ALS and frontotemporal dementia (FTD) in mice -- and may even offer the potential to reverse some of the effects of the fatal diseases. It may also hold opportunities for treating more common forms of dementia, such as Alzheimer's disease. The new treatment, dubbed CTx1000, targets pathological build-ups of the protein TDP-43 in cells in the brain and spinal cord, which has been It has been associated with ALS, FTD and other forms of dementia. The Macquarie University research team, led by Professor Lars Ittner, hopes to see CTx1000 begin human clinical trials in as little as two years. Cells like neurons produce TDP‑43 naturally, and it is important for their healthy function. Under certain conditions, it accumulates in the wrong part of the cells, clogging them and preventing them from working properly. For the past 15 years, a Macquarie University research team led by Professor Lars Ittner has been looking for the causes of this pathological build-up of TDP-43, along with ways to clear the blockages and prevent them from forming in the first place. Professor Ittner says their research has furthered their understanding of MND and FTD and their causes. "We discovered for the first time that where there is pathological TDP-43, there is also an increase in a second protein, 14‑3‑3," he says. "The two proteins interact, resulting in these build-ups in the cells," he says. "From this, we were able to isolate a short peptide that controls this interaction, and that's what we used to create CTx1000. "When we administered it in the lab, it dissolved the build-ups, tagging TDP-43 proteins for recycling by the body, and prevented new ones from forming. "Importantly, CTx1000 targets only pathological TDP-43, allowing the healthy version of the protein to be produced and go about its work unhindered." Professor Ittner says this makes CTx1000 incredibly safe, and they have seen no adverse effects in their studies. Lead author of the paper, Professor Yazi Ke, says in lab conditions, CTx1000 stopped ALS and FTD from progressing even at very advanced stages, and resolved the behavioural symptoms associated with FTD. "We have great hopes that when this progresses to human trials, it will not only stop people from dying from both ALS and FTD, but even allow patients to regaining some of the lost function through rehabilitation," she says. CTx1000 is one of the key discoveries being championed by Celosia Therapeutics, a Macquarie University spin-out company formed in 2022 to help bring the groundbreaking work of the University's neuroscientists from the lab to patients. Celosia Therapeutics is actively seeking investment to facilitate CTx1000 to progress to clinical trial stage. About ALS and FTD Also known as motor neuron disease (MND), ALS causes the progressive loss of the neurons that allow the brain and spine to communicate with the muscles. In its early stages, patients experience muscle weakness, but as the disease progresses, they gradually lose the ability to walk, speak, swallow and breathe unaided. Most people with ALS die within two to five years of diagnosis. While there is a genetic therapy showing promise for one form of familial ALS, there are few treatments available for the sporadic ALS that makes up 90 per cent of all cases. Of those, the most effective can only extend a patient's life by up to five months. All require frequent doses, and some come with side effects that are difficult to cope with. FTD is one of the rarer forms of dementia, but it is the second-most common form in people younger than 65. Actor Bruce Willis was diagnosed with FTD in 2023. It does not always have obvious physical symptoms, but it results in cognitive decline coupled with behavioural symptoms including anxiety, loss of inhibition, personality change, and impaired judgment. Patients may live for more than 10 years after diagnosis, but it is ultimately fatal. There is currently no treatment for FTD.

Chk1, also known as checkpoint kinase 1, is a crucial protein kinase involved in the regulation of cell cycle progression and DNA damage response in the human body.  Chk1 is a serine/threonine (Ser/Thr) kinase encoded by the tumor suppressor gene Chk1, broadly existing in mammalian cells. In recent years, numerous domestic and international studies have indicated that Chk1 and its inhibitors can regulate the formation and development of tumors. Chk1 controls cell proliferation, being the key gene leading to an S/G1 and G2/M phase arrest after DNA damage, thus ensuring DNA repair and having vital surveillance function. Overexpression of Chk1 is observed in a variety of tumor tissues; it can participate in the onset and progression of certain tumors through specific molecular signaling pathways, and its aberrant expression levels are closely related to the therapeutic effects and prognosis of patients with hematological tumors. High expression of Chk1 is of great significance in the infiltration and metastasis of hematological tumor cells, and the appearance of Chk1 inhibitors provides a new direction for the treatment of malignant blood tumors. It plays a vital role in ensuring the integrity of the genome by monitoring DNA replication and repair processes. Chk1 acts as a checkpoint mediator, halting cell cycle progression in response to DNA damage or replication stress, allowing time for repair mechanisms to be activated. Dysregulation of Chk1 has been implicated in various diseases, including cancer, making it an attractive target for pharmaceutical interventions aimed at enhancing the efficacy of DNA-damaging therapies or developing novel anticancer treatments. So far, over 10 types of CHK1 inhibitors have entered clinical research, but no CHK1 inhibitor has been approved for marketing. Most CHK1 inhibitors have ceased development due to issues of efficacy and safety, and most of these compounds are administered through injections. Of the 4 types of CHK1 inhibitors that are currently still under clinical research, besides LY2606368, GDC0575, LY2880070, and CCT245737 can all be administered orally, greatly improving patient compliance. Therefore, the development of highly active, highly selective, and orally administrable new CHK1 inhibitors is an important direction for research in this field. Studies have found that the absence of FAM122A can promote tumor cell resistance to CHK1 and ATR inhibitors. Further research showed that CHK1 can phosphorylate the S37 site of FAM122A, which makes it move out of the nucleus and bind with 14-3-3, inhibiting its binding with the PP2A-B55α phosphatase complex, thereby improving the stability of WEE1 protein. Similarly, the absence of FAM122A will also increase the stability of WEE1 protein, activate the G2/M checkpoint, and prevent cells with DNA damage from entering mitosis, achieving resistance. Chk1 Competitive LandscapeAccording to Patsnap Synapse, as of 27 Sep 2023, there are a total of 30 Chk1 drugs worldwide, from 40 organizations, covering 42 indications, and conducting 79 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target.  Based on the analysis of the provided data, the current competitive landscape of target Chk1 shows that Eli Lilly & Co., Pfizer Inc., GSK Plc, and Baylor University are the companies with the highest development stages. Ovarian Cancer and Uterine Cervical Cancer are the indications with the most drugs in phase 2 development. Small molecule drugs are progressing rapidly under the current target, with a significant number of drugs in both phase 2 and preclinical stages. The United States, United Kingdom, and European Union are the countries/locations with the highest development stages, while China also shows progress in phase 1 development. Overall, the target Chk1 presents opportunities for further research and development in various indications and drug types, with a focus on small molecule drugs.

For a drug to work, the molecule must bind to its target. That’s tricky for elusive targets lacking typical binding sites, but that hurdle can be overcome with molecular glue, a molecule that brings together two proteins that don’t normally interact. Molecular glues are a hot area of research in the context of targeted protein degradation, an emerging therapeutic approach that gets a disease-causing protein to go to the cell’s built-in protein disposal system. A molecular glue ensures that the enzyme tag marking a protein for disposal sticks to the target protein. Biotech companies have reached the clinic with this type of drug, but they’re all degraders. Brian Safina, president and chief scientific officer of Magnet Biomedicines, says molecular glues can do more, and the startup is now out of stealth to show how. “It’s really all focused on degradation,” Safina said of current molecular glue research. “While that’s a great way to go, there are other biological mechanisms that one can take advantage of.” Boston-based Magnet formally launched on Tuesday, backed by $50 million. The Series A financing was co-led by Newpath partners, which was the startup’s founding and initial investor, and Arch Venture Partners. Molecular glues are already available via some old and widely prescribed medicines, such as cyclosporine A and rapamycin, Safina said. But as is the case with many older drugs, the mechanism of both immunosuppressants was not known at first. In the early 1990s, Stuart Schreiber, a Harvard University professor of chemistry and biology, revealed cyclosporin works as a molecular glue that induces protein-protein interactions. Schreiber has founded or co-founded biotech startups such as Jnana Therapeutics, Forma Therapeutics, and Belharra Therapeutics. Magnet, which Schreiber also co-founded, builds on the scientist’s decades of molecular glue research while also taking the therapeutic modality beyond degradation, Safina said. “Now with degraders making inroads into disease and showing impact, Stuart found the time is right to expand beyond that in molecular discovery,” he said. Rather than finding molecular glues by chance, Magnet takes a rational approach to discovering them. The company screens chemical libraries and analyzes human genetics and protein data to identify its molecular glues. Safina says his company’s molecules, called TrueGlues, prompt “cooperative interaction” between proteins. Safina declined to disclose any of Magnet’s targets, though he said the company is initially focusing on targets that already have clinical and genetic validation. Therapeutic areas falling within that scope include immunology, oncology, and cardiovascular disease. The TrueGlue platform is indication agnostic, and that broad potential positions Magnet for partnering opportunities, Safina said. He added that the company is researching areas where “there is an opportunity to have a molecular glue to solve some of the problems that exist.” What are those problems? A targeted protein degrader molecule resembles a barbell, with each end having a different function. But Safina says these bifunctional molecules are challenging to develop as oral formulations. A molecular glue can also imbue a Magnet drug with high specificity to its target, similar to the targeting ability of antibodies. Higher specificity reduces the risk of adverse effects that happen when a drug goes off target. Magnet joins a growing group of companies researching molecular glues. Monte Rosa Therapeutics, which trades under the descriptive stock symbol “GLUE,” develops molecular glues for applications in targeted protein degradation. The Boston-based company’s most advanced program is in early clinical development for various cancers. Ambagon Therapeutics launched last year to develop glues that address the 14-3-3 family of proteins. Those glues can work in a variety of ways, such as stabilizing protein interactions, inhibiting function, restoring function, or protein degradation. The San Francisco-based startup’s preclinical pipeline currently spans six programs in cancer and one in neurodegeneration. Meanwhile, A-Alpha Bio discovers molecular glues that other companies use in their drug research. Disclosed partners of Seattle-based A-Alpha include Bristol Myers Squibb, Kymera Therapeutics, and Gilead Sciences. Magnet drugs could work in a variety of ways. While targeted protein degradation is one potential mechanism, Safina reemphasized that Magnet aims to expand beyond degradation. The startup’s drugs could inhibit function like traditional small molecules. A Magnet drug could also stabilize a target protein. Safina said Magnet’s technology should produce drugs capable of binding to targets that are tough for small molecules. Magnet will use its new capital to continue building the TrueGlue platform while applying it to a variety of targets. Safina said the Series A round will enable the startup to reach lead optimization with understanding of which types of targets are most amenable to the TrueGlue approach. The financing will also support the company through candidate nomination and preparation for an investigational new drug application, he said.