TRPM2

Two of Caraway Therapeutics' preclinical candidates are compounds designed to modulate TRPML1, an ion channel that is shown to be dysregulated in neurodegenerative diseases. Merck & Co. has made no secret of its ongoing hunt for acquisitions, and, now, the Big Pharma is rounding off the year by swelling its preclinical pipeline with a selection of programs aimed at Parkinson’s disease and beyond. The New Jersey company has signed off on up to $610 million in combined upfront payment and potential milestones to buy Caraway Therapeutics—although no breakdown of the exact costs was given in the relatively sparse Nov. 21 release. Originally named Rheostat Therapeutics, the company was incubated at SV Health Investors and the Dementia Discovery Fund before arriving on the scene in 2018 with $23 million in series A funding. Merck has been a backer from the start, having co-led that funding round along with AbbVie. Rebranding to Caraway the following year, the Cambridge, Massachusetts-based company billed itself as a “leader in the cutting-edge science of activating autophagy, the cellular recycling processes to clear toxic materials and defective cellular components.” Since the rebrand, the biotech hasn’t made much noise, but the company’s website currently lists four programs in the works, none of which have entered the clinic. They include two different compounds designed to modulate TRPML1, a transient receptor potential ion channel that is shown to be dysregulated in neurodegenerative diseases. One of the compounds is being developed for Parkinson’s associated with a mutated GBA gene, while the other is focused on non-central nervous system rare diseases. Also in the pipeline is a TMEM175 modulator designed to increase activity of this lysosomal potassium channel in patients with Parkinson’s or amyotrophic lateral sclerosis. There is also another potential Parkinson’s drug that remains in the discovery stage. Merck already made an M&A splash this year with the almost $11 billion acquisition of Prometheus Biosciences and its late-phase bowel disease drug, followed by a $4 billion payment last month to secure three antibody-drug conjugates from Daiichi Sankyo. As the Big Pharma continues to plot out its post-Keytruda future, executives have been open about the ongoing need to refill the pipeline this year. “Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” George Addona, Ph.D., senior vice president of discovery, preclinical development and translational medicine at Merck Research Laboratories, said in this morning’s release. “We look forward to applying our expertise to build upon this work with the goal of developing much needed disease-modifying therapies for these conditions,” Addona added.

Researchers induced a hibernation-like state in mice by using ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. The findings show the first noninvasive and safe method to induce such a state; a similar condition has been previously proposed for spaceflight or for patients with life-threatening health conditions. Some mammals and birds have a clever way to preserve energy and heat by going into torpor, during which their body temperature and metabolic rate drop to allow them to survive potentially fatal conditions in the environment, such as extreme cold or lack of food. While a similar condition was proposed for scientists making flights to space in the 1960s or for patients with life-threatening health conditions, safely inducing such a state remains elusive. Hong Chen, an associate professor at Washington University in St. Louis, and a multidisciplinary team induced a torpor-like state in mice by using ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. In addition to the mouse, which naturally goes into torpor, Chen and her team induced torpor in a rat, which does not. Their findings, published May 25, 2023, in Nature Metabolism, show the first noninvasive and safe method to induce a torpor-like state by targeting the central nervous system. Chen, associate professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, and her team, including Yaoheng (Mack) Yang, a postdoctoral research associate, created a wearable ultrasound transducer to stimulate the neurons in the hypothalamus preoptic area. When stimulated, the mice showed a drop in body temperature of about 3 degrees C for about one hour. In addition, the mice's metabolism showed a change from using both carbohydrates and fat for energy to only fat, a key feature of torpor, and their heart rates fell by about 47%, all while at room temperature. The team also found that as the acoustic pressure and duration of the ultrasound increased, so did the depth of the lower body temperature and slower metabolism, known as ultrasound-induced hypothermia and hypometabolism (UIH). "We developed an automatic closed-loop feedback controller to achieve long-duration and stable ultrasound-induced hypothermia and hypometabolism by controlling of the ultrasound output," Chen said. "The closed-loop feedback controller set the desired body temperature to be lower than 34C, which was previously reported as critical for natural torpor in mice. This feedback-controlled UIH kept the mouse body temperature at 32.95C for about 24 hours and recovered to normal temperature after ultrasound was off." To learn how ultrasound-induced hypothermia and hypometabolism is activated, the team studied the dynamics of the activity of neurons in the hypothalamus preoptic area in response to ultrasound. They observed a consistent increase in neuronal activity in response to each ultrasound pulse, which aligned with the changes in body temperature in the mice. "These findings revealed that UIH was evoked by ultrasound activation of hypothalamus preoptic area neurons," Yang said. "Our finding that transcranial stimulation of the hypothalamus preoptic area was sufficient to induce UIH revealed the critical role of this area in orchestrating a torpor-like state in mice." Chen and her team also wanted to find the molecule that allowed these neurons to activate with ultrasound. Through genetic sequencing, they found that ultrasound activated the TRPM2 ion channel in the hypothalamus preoptic area neurons. In a variety of experiments, they showed that TRPM2 is an ultrasound-sensitive ion channel and contributed to the induction of UIH. In the rat, which does not naturally go into torpor or hibernation, the team delivered ultrasound to the hypothalamus preoptic area and found a decrease in skin temperature, particularly in the brown adipose tissue region, as well as about a 1 degree C drop in core body temperature, resembling natural torpor. This multidisciplinary team consists of Jonathan R. Brestoff, MD, PhD, assistant professor of pathology & immunology at the School of Medicine; Alexxai V. Kravitz, associate professor of psychiatry, of anesthesiology and of neuroscience at the School of Medicine, and Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering, all at Washington University in St. Louis. The team also includes Michael R. Bruchas, professor of anesthesiology and of pharmacology at the University of Washington. "UIH has the potential to address the long sought-after goal of achieving noninvasive and safe induction of the torpor-like state, which has been pursued by the scientific community at least since the 1960s," Chen said. "Ultrasound stimulation possesses a unique capability to noninvasively reach deep brain regions with high spatial and temporal precision in animal and human brains." This work was supported by the National Institutes of Health (R01MH116981, UG3MH126861, R01EB027223, and R01EB030102). JRB is supported by NIH (DP5 OD028125) and Burroughs Wellcome Fund (CAMS #1019648).