Tag: Biotech

The scientists responsible for developing sonogenetics, which refers to the application of low-intensity ultrasound to noninvasively achieve precise control of cellular proteins, have secured an influx of federal funding that will allow them and their collaborators transform the technology into a potential therapy for various conditions starting with peripheral neuropathies.

Late last week, Salk Institute for Biological Studies announced that Sreekanth Chalasani, PhD, an associate professor in Salk’s molecular neurobiology laboratory, and his partners in collaborating laboratories elsewhere, were awarded $41.3 million from the Advanced Research Projects Agency for Health (ARPA-H), an agency within the United States Department of Health and Human Services. Working on multiple fronts over the next five years, the partners will develop core biological tools and ultrasound delivery systems while generating the preclinical evidence needed to move sonogenetics into human clinical trials. 

“This award is a major step toward a long-held goal—a drug-free way to deliver therapy exactly where it’s needed and only when it’s needed,” said Chalasani, who serves as the principal investigator for the grant and is also the co-founder of SonoNeu, a startup launched to commercialize therapies based on the technology. Key to accomplishing that goal is “a platform that pairs engineered ultrasound-sensitive proteins with wearable ultrasound technology, which, unlike conventional pharmaceutical treatments, could let us treat conditions with cellular and temporal control.” 

Reaching cells through sound

In 2011, armed with support from Salk’s Innovation and Collaboration Grants program, Chalasani and his team pioneered sonogenetics, a technique for sensitizing specific cell types to ultrasound by equipping them with ultrasound-responsive proteins. In 2015, his group first identified a particular protein in the roundworm Caenorhabditis elegans (C. elegans) that makes cells sensitive to low-frequency ultrasound. When they added this protein to C. elegans neurons that did not usually have it, they were able to activate these cells using ultrasound waves. 

Since that initial discovery, Chalasani’s team and others have shown that they can use sonogenetics to manipulate mammalian cells. Some of their work was published in a 2022 Nature Communications paper which describes efforts to engineer a human channel protein in cultured mammalian cells and living animal models to confer cell-specific sensitivity to ultrasound stimulation.

Chalasani noted in an interview with GEN that the pace of their progress from an idea to potential clinical translation in the span of about 15 years is remarkable, compared to the typical multi-decade timeline for most new therapies. “In terms of how quickly this has gone from a [research] idea to what patients should we look at [and] how are we going to help them? The pace has been overwhelming,” he said. He attributed much of that progress to the work of the trainees, post-doctoral students, and collaborators through the years who were willing to take on “this crazy idea and work on this project, even though there was no guarantee it would get anywhere.” He also highlighted the early investment from Salk and other entities including the National Institutes of Health’s Brain Initiative as key to project’s success.  

Though Chalasani and his lab pioneered sonogenetics, the next phase of its development is not a solo effort. It involves a multiple institutions and teams all of whom are contributing essential and specialized expertise. The list of collaborators includes Scripps Research, where a team led by 2021 Nobel Laureate Ardem Patapoutian, PhD, will support the discovery and engineering of ultrasound-sensitive proteins. Then a team at St. Boniface Hospital Research and the University of Manitoba led by Paul Fernyhough, PhD, will help define how ultrasound-triggered signals move through cellular machinery and drive nerve repair pathways.

Another team, led by Aravind Asokan, PhD, at Duke University will work on targeted vectors for delivering ultrasound-sensitive proteins to specific cell types. Separately, a team led by Xuanhe Zhao, PhD, at Massachusetts Institute of Technology will work on targeted mechanisms for delivering ultrasound to animal and human targets. Then scientists at the University of California, San Diego, led by Nigel Calcutt, PhD, will validate the efficacy of sonogenetics across established paradigms and in mammalian systems. Finally, Ghassan Kassab, PhD, and his team at California Medical Innovations Institute, will support advanced translational validation and clinically relevant assessment in preclinical systems. 

For their part, Chalasani and his team at Salk will work on finding additional actuators or sensors for ultrasound that will be optimized for targeted delivery. “What we have are proteins that can respond to that small amount of mechanical deflection that ultrasound can cause,” Chalasani explained. “These proteins are channels [that] sit on the membrane of the cell and when the cell experiences ultrasound, the protein gets activated, it opens up, and allows calcium [for example] into the cell. Because these proteins can actuate an effect, they are called ultrasound actuators.” 

Currently, the group has identified proteins that can move things like calcium and chloride into cells in response to ultrasound but they are hunting for other proteins that can activate various signaling pathways. Besides new actuators, the Salk scientists will work on validation studies in mouse models, and lay the groundwork for experiments in larger animal models, specifically pigs, Chalasani told GEN. 

There is a plan in place to commercialize therapies developed using sonogenetics technology. Salk spinout SonoNeu will receive a portion of the ARPA-H funding to help  move potential therapies through the regulatory process and commercialization. Chalasani is listed as a co-founder as is Venkat Reddy, chief scientific officer of General Inception, a firm that partners with scientific founders to build their companies. The target, Chalasani said, is to have something ready for the U.S. Food and Drug Administration in the next five years. 

The initial treatment target condition is peripheral neuropathies and in that context, “there are a lot of interesting places for us to evaluate,” he said. “But I think the real question is going to be what pathway are we targeting? We can do calcium and chloride [but] is that enough to get a therapeutic benefit in a patient or should we have to activate something else other than that? Do we have to activate an enzyme [or] a kinase? And how would we do that? Can we link these proteins to those signals? So there are some unknowns here.”  

If all goes well, other patient populations could benefit from sonogenetics-based therapies besides peripheral neuropathies including people with diabetes, heart conditions or it could help with bladder control, Chalasani said. There are even possible applications in the context of brain-computer interfaces. 

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Animal behavior reflects a complex interplay between an animal’s brain and its sensory surroundings. In a new study published in Nature Neuroscience titled, “Neural sequences underlying directed turning in Caenorhabditis elegans,” researchers from Massachusetts Institute of Technology (MIT) have shown how neuron circuits within C. elegans nematode worms respond to odors and generate movement as they pursue favorable versus unfavorable smells. The results inform understanding of the basic principles of the sensory nervous system for therapeutic applications. 

“Across the animal kingdom, there are just so many remarkable behaviors,” said Steven Flavell, PhD, associate professor at the Picower Institute at MIT, Howard Hughes Medical Institute (HHMI) investigator, and corresponding author of the study. “With modern neuroscience tools, we are finally gaining the ability to map their mechanistic underpinnings.” 

Whether moving toward a food source or away from a predator, animals must integrate sensory stimuli to navigate to favorable locations. The neural circuits for navigation are tasked with generating directed movement while simultaneously integrating sensory input to update behavior. Understanding how neural circuits select, execute and adapt sensory-guided navigation behaviors uncovers basic principles of how nervous systems are organized to integrate sensory information and control behavior. 

In C. elegans, the authors identified error-correcting turns during navigation and used whole-brain calcium imaging and cell-specific perturbations to determine their neural underpinnings. Defined neurons activated in a stereotyped order during each turn. Distinct neurons in this sequence respond to the spatial distribution of attractive and aversive olfactory cues, anticipate upcoming turn directions and drive movement, linking key features of this sensorimotor behavior across time. 

“One thing that really excited us about this study is that we were able to see what a sensorimotor arc looks like at the scale of a whole nervous system: all the bits and pieces, from responses to the sensory cue until the behavioral response is implemented,” Flavell said.  

The electrical activity of more than 100 neurons was tracked during sensory movement. Notably, C. elegans only have 302 neurons total. Instead of random movements, the worms executed turns with advantageous timing and at well-chosen angles.  

The activity of SAA neurons was crucial for integrating odor detection with planned movement and predicted the direction of upcoming turns. Several neurons showed different activity patterns depending on the location of odors were and whether the worm was moving forward or in reverse. 

Additionally, the neuromodulator, tyramine, was essential for turning and shifting gears. When the worms moved in reverse, tyramine from the neuron RIM enabled other neurons in the sequence to change their activity appropriately to execute the turns. In several experiments, the scientists knocked out RIM tyramine, which disrupted the navigation behaviors and the sequence of neural activity. 

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