TAF1

THURSDAY, March 30, 2023 -- Cluster headache and migraine are highly circadian, according to a review published online March 29 in Neurology . Barlas Benkli, M.D., from UT Health Houston, and colleagues conducted a systematic review of 72 studies to examine circadian features of cluster headache and migraine. In addition, a genetic analysis for genes with a circadian pattern of expression (clock controlled genes [CCGs]) was conducted by cross-referencing 16 genome-wide association studies of headache, one nonhuman primate study of CCGs in various tissues, and 16 imaging reviews of brain areas relevant in headache disorders. The researchers found that for cluster headache, a meta-analysis across 16 studies showed a circadian pattern of attacks in 70.5 percent of participants, with a clear circadian peak between 21.00 and 03.00, and with circannual peaks in spring and autumn. Across studies, chronotype was highly variable. Lower melatonin and higher cortisol levels were reported at the systems level. Cluster headache was associated with core circadian genes CLOCK and REV-ERB α at the cellular level; five of nine cluster headache susceptibility genes were CCGs. For migraine, 50.1 percent of participants across eight studies showed a clear circadian pattern of attacks, with a clear circadian trough between 23.00 and 07.00, and a broad circannual peak between April and October. Across studies, chronotype was highly variable. Urinary melatonin levels were lower in migraine participants at the systems level and were even lower during an attack. Migraine was associated with core circadian genes CK1δ and RORα at the cellular level; 110 of 168 migraine susceptibility genes were CCGs. "These results raise the potential for using circadian-based treatments for headache disorders," a coauthor said in a statement. One author disclosed financial ties to Lundbeck. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted March 2023

Award from MGH CCXDP advances effort to identify new treatments for X-linked dystonia Parkinsonism (XDP) BOSTON, March 29, 2023 /PRNewswire/ -- Unravel Biosciences, Inc., ("Unravel"), a therapeutics company that leverages a machine-learning model of human health to advance drugs for complex diseases, today announced receipt of grant funding from the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP) at Massachusetts General Hospital (MGH) to enable rapid target discovery for XDP. The MGH award will allow for a significant expansion of research effort that follows on the successful completion of work funded by an earlier grant that supported development of whole-organism models of XDP through TAF1 gene CRISPR editing and drug candidate screening. In the earlier project funded by MGH CCXDP, Unravel successfully demonstrated XDP model creation in under 3 weeks using Xenopus tadpoles engineered with Unravel's proprietary "SquishyWare™" disease model generation process. Additionally, Unravel's BioNAV™ AI prediction platform identified a novel therapeutic mechanism and candidate compound that led to broad rescue of the tadpole XDP phenotype. The current award will advance target discovery and validation to enable new drug development tailored to the needs to XDP patients. "We are pleased with the opportunity to continue this collaboration with CCXDP," said Frederic Vigneault, Ph.D., Unravel Co-Founder and CSO. "The expansion of our collaboration with MGH is a great validation of the power of our scientific platform and its potential to expedite the identification of promising therapeutic compounds to take into the clinic. Within a year, our computational and biology teams have homed in on specific and novel therapeutic mechanisms. Our ambition by the end of this grant is to nominate a candidate that can move quickly to clinical trials." XDP is a severe adult-onset neurodegenerative disease that causes progressive dystonia and Parkinsonian symptoms. Patients experience worsening motor control and a significantly shorter lifespan. The disease is linked to a DNA repeat expansion within an intron in the TAF1 gene that disrupts TAF1 splicing and reduces levels of the full-length transcript. XDP currently lacks an approved treatment. About Unravel Biosciences Unravel Biosciences is a personalized therapeutics company that redefines diseases through RNA network analysis to seamlessly bridge target discovery with clinical efficacy of new drugs. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases impacting the whole body. Unravel's platform discovered RVL001, a proprietary formulation targeting Rett Syndrome that will enter the clinic this year, and RVL002, a new small molecule with applications in CNS and metabolic diseases. . SOURCE Unravel Biosciences, Inc.

Award from MGH CCXDP advances effort to identify new treatments for X-linked dystonia Parkinsonism (XDP) BOSTON, March 29, 2023 /PRNewswire/ -- Unravel Biosciences, Inc., ("Unravel"), a therapeutics company that leverages a machine-learning model of human health to advance drugs for complex diseases, today announced receipt of grant funding from the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP) at Massachusetts General Hospital (MGH) to enable rapid target discovery for XDP. The MGH award will allow for a significant expansion of research effort that follows on the successful completion of work funded by an earlier grant that supported development of whole-organism models of XDP through TAF1 gene CRISPR editing and drug candidate screening. In the earlier project funded by MGH CCXDP, Unravel successfully demonstrated XDP model creation in under 3 weeks using Xenopus tadpoles engineered with Unravel's proprietary "SquishyWare™" disease model generation process. Additionally, Unravel's BioNAV™ AI prediction platform identified a novel therapeutic mechanism and candidate compound that led to broad rescue of the tadpole XDP phenotype. The current award will advance target discovery and validation to enable new drug development tailored to the needs to XDP patients. "We are pleased with the opportunity to continue this collaboration with CCXDP," said Frederic Vigneault, Ph.D., Unravel Co-Founder and CSO. "The expansion of our collaboration with MGH is a great validation of the power of our scientific platform and its potential to expedite the identification of promising therapeutic compounds to take into the clinic. Within a year, our computational and biology teams have homed in on specific and novel therapeutic mechanisms. Our ambition by the end of this grant is to nominate a candidate that can move quickly to clinical trials." XDP is a severe adult-onset neurodegenerative disease that causes progressive dystonia and Parkinsonian symptoms. Patients experience worsening motor control and a significantly shorter lifespan. The disease is linked to a DNA repeat expansion within an intron in the TAF1 gene that disrupts TAF1 splicing and reduces levels of the full-length transcript. XDP currently lacks an approved treatment. About Unravel Biosciences Unravel Biosciences is a personalized therapeutics company that redefines diseases through RNA network analysis to seamlessly bridge target discovery with clinical efficacy of new drugs. Unravel leverages its proprietary BioNAV™ platform combining target and drug discovery, preclinical screening and patient stratification to find treatments for complex diseases impacting the whole body. Unravel's platform discovered RVL001, a proprietary formulation targeting Rett Syndrome that will enter the clinic this year, and RVL002, a new small molecule with applications in CNS and metabolic diseases. . View original content to download multimedia: SOURCE Unravel Biosciences, Inc.