TRPC5

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. The discovery, reported today in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms. Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. The discovery, reported today in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms. Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization. While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome. Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. The mothers also had obesity, but in addition had experienced postnatal depression. To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice). Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour. Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine, said: "What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours." TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite. When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons -- nerve cells that produce the hormone oxytocin, often nicknamed the 'love hormone' because of its release in response to displays of affection, emotion and bonding. Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression. In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age. Professor Sadaf Farooqi from the Institute of Metabolic Science at the University of Cambridge said: "There's a reason why people lacking TRPC5 develop all of these conditions. We've known for a long time that the hypothalamus plays a key role in regulating 'instinctive behaviours' -- which enable humans and animals to survive -- such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts." While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people -- around three-quarters of whom were women -- that carried variants of the gene and had a higher-than-average body mass index. The researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression. Professor Farooqi said: "While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition." There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. The team say their work provides direct proof of oxytocin's role, which will be crucial in supporting bigger, multi-centre trials. Professor Farooqi added: "This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that's our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions." This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Neurological drugs developer Karuna Therapeutics is building up its pipeline with a pair of molecules initially developed for kidney disorders. It’s a small bet that could pay off in a big way by diversifying its pipeline with medicines that could compete against a Boehringer Ingelheim drug candidate addressing the same target. The new Karuna assets come from startup Goldfinch Bio, which is shutting down. According to financial terms announced Thursday, Boston-based Karuna is paying $15 million up front for both small molecules. Goldfinch discovered drugs with technology that analyzed anonymized human kidney data in order to identify potential drug targets. That technology identified ways to target transient receptor potential canonical (TRPC) channels 4 and 5, pathways associated with certain kidney disorders. The research yielded lead program GFB-887, which reached mid-stage testing. While activity was shown in the kidney, Karuna President of Research & Development and Chief Scientific Officer Steve Paul notes that the preclinical and clinical research also showed antidepressant and anxiety-reducing properties. “We are fortunate to have found as advanced a clinical-stage drug candidate directed against these important [central nervous system] targets and we will now study GFB-887 in various mood and anxiety disorders where there remains a significant unmet medical need for mechanistically novel medicines,” Paul said in a prepared statement. Going after TRPC 4/5 brings a different dimension to Karuna, which has focused its research on targeting muscarinic receptors found in the central nervous system. Lead drug candidate KarXT, an agonist of two muscarinic receptors, M1 and M4, reached Phase 3 testing in schizophrenia. After posting positive data in the study last August, the biotech said it planned to seek FDA approval in mid-2023. The remaining programs are preclinical and are in development for undisclosed targets. Karuna said it expects to report more details on the plans for GFB-887 in the second half of this year. By then, Boehringer Ingelheim could have Phase 2 data for its drug candidate targeting TRPC4/5 in depression. A positive result in that study could read through to Karuna’s new assets, William Blair analyst Myles Minter wrote in a research note. He added that to his knowledge, Karuna now has the only other TRPC4/5 inhibitors in development for neuropsychiatric disorders and it could have a dosing edge—once daily compared to the twice-a-day dosing of the Boehringer Ingelheim drug candidate. The $15 million upfront payment is minor for what has the potential to become a high-value asset, Minter said. Depending on the progress of the research, Karuna could pay up to $520 million in milestone payments for each TRPC4/5 drug candidate. The biotech would also pay the Goldfinch estate royalties from sales if the molecules reach the market. Goldfinch, which spun out of venture capital firm Third Rock Ventures, initially tested GFB-887 in focal segmental glomerulosclerosis (FSGS), a rare disorder that leads to scar tissue on renal glomeruli, the parts of the kidney that filter waste from the blood. Nearly a year ago, the company reported mixed preliminary Phase 2 data for the drug. While the results showed reductions in levels of urine proteins indicative of FSGS, no treatment effect was observed in the initial group of diabetic nephropathy patients. Fierce Biotech was first to report last week that Goldfinch was shutting down. Executives told Fierce that the move follows the company’s failure to secure additional financing.

Karuna Therapeutics is potentially betting hundreds of millions of dollars on the idea that a shuttering drugmakers experimental medicines for kidney diseases could become useful treatments for psychiatric and neurological disorders.Through a deal announced Thursday, Karuna will get an exclusive global license to develop, manufacture and market these medicines from Goldfinch Bio, which target a type of protein known as transient receptor potential channels. Goldfinchs most advanced drug, GFB-887, has been studied in mid-stage clinical trials that tested it across several kidney illnesses, including diabetic nephropathy and focal segmental glomerulosclerosis.According to reporting from Fierce Biotech, Goldfinch is going out of business after failing to secure additional funding. The Cambridge, Massachusetts-based company launched in late 2016 with $55 million from Third Rock Ventures and a mission to usher in a new era of therapeutic development targeting the molecular basis of progressive kidney diseases.Goldfinchs work later attracted the attention of Gilead Sciences, which, in the spring of 2019, agreed to a multiyear collaboration focused on diabetic kidney disease as well as orphan kidney disorders. The heavily backloaded agreement carried a nearly $110 million upfront payment for the smaller company.About a year after announcing the Gilead deal, Goldfinch secured another $100 million in a financing round led by Eventide Asset Management. Gilead also participated in the round, as did new investors like Wellington Management and Ally Bridge Group.Yet, like many biotechnology companies with big ambitions, Goldfinch has faced setbacks. Last year, for instance, one of the studies testing GFB-887 delivered mixed results. And since then, a historic downturn in the biotech sector made it far more challenging for Goldfinch and many others to raise money.“Unfortunately, we had funding challenges, just like I think the rest of the environment, particularly private companies, in the current macro environment,“ Tony Johnson, Goldfinchs CEO, told Fierce Biotech.With the Karuna deal, Goldfinch, through the assignee of its assignment estate, will receive $15 million upfront. It is also eligible for up to $520 million in milestone payments for each candidate that gets licensed.Specifically, the deal gives Karuna access to drugs directed at the protein channels TRPC4 and TRPC5, which the company believes could have beneficial applications in the brain. Karuna said it intends to study GFB-887 for the treatment of mood and anxiety disorders, and will share more details on the drugs development plans in the second half of this year.So far, Karunas research efforts have largely revolved around KarXT, an experimental therapy that clinical trials showed to be helpful in the treatment of schizophrenia. Karuna expects this year to ask the Food and Drug Administration to approve KarXT, and is also evaluating the therapy in patients with Alzheimers disease psychosis.Goldfinchs medicines therefore help to diversify Karunas research.We believe that the TRPC4/5 mechanism could represent a completely novel approach to treating mood and anxiety disorders and complements our existing pipeline, Bill Meury, Karunas newly minted CEO, said in a statement.Meury added that the Goldfinch agreement aligns with our strategic goal to become a fully integrated neuroscience company with treatments that could offer much more than just incremental benefits to patients. '