The Next Leap in Genetic Medicine 

SonoThera’s novel technology could unleash new genetic medicines with expanded patient access. 

In theory, genetic therapies could treat many diseases: rare monogenic conditions, more common and complex cardiovascular and metabolic issues, neurodegenerative diseases, and cancer. Unfortunately, the reality has been disappointing. Early gene therapies have been plagued with mixed efficacy, off-target effects, and other issues. 

These shortcomings often revolve around delivery – the ability to transfer genetic payloads to the right tissues. Adeno-associated viruses (AAVs) have emerged as a favored delivery system but have had numerous problems, including safety, the inability to hit certain targets, and high costs. Lipid nanoparticles (LNPs) offer an alternative but have also fallen short. The industry has needed new approaches that safely, effectively, and cost-effectively fulfill gene therapy’s outstanding promise.  

SonoThera was founded to fill that gap. The company is developing genetic therapies that combine microbubbles and ultrasound, two well-established technologies, that precisely target the appropriate tissues. 

“By removing the delivery barriers that have limited gene therapy, SonoThera opens up new opportunities to treat multiple diseases,” said Tom Willis, Partner at Illumina Ventures. “This approach could accommodate larger genetic payloads and treat organs that AAVs and LNPs simply can’t touch in a redosable, safe, and economical manner.” 

 

A Meeting of Minds 

SonoThera’s co-founder and CEO, Ken Greenberg, Ph.D., began working on gene therapy in 2001, not long after some high-profile treatment failures. Several people suggested he shift to a different discipline, but Greenberg was undeterred. 

Over the years, he worked with numerous viral delivery platforms and cofounded two gene therapy companies, learning first-hand about viral vector limitations. Later, he met his SonoThera cofounders, cardiologists Steve Feinstein, M.D. and Michael Davidson, M.D. 

Feinstein, who is now SonoThera’s chief scientific officer, invented the first two FDA-approved ultrasound contrast agents, commonly called microbubbles. About the same size as red blood cells, microbubbles can move freely around the body, helping clinicians image the heart and other organs.  

Feinstein and Davidson, SonoThera’s executive chairman, realized microbubbles could also act as a delivery system. Adding Greenberg’s gene therapy and entrepreneurial expertise, they founded SonoThera. 

“By the time I met Steve and Michael, they had generated some very exciting proof of concept data, on a shoestring budget, showing they could selectively deliver genetic payloads to different organs,” said Greenberg. “I was captivated because their approach could potentially address many of the delivery challenges that had limited the field of genetic medicine.”  

 

Dealing With Delivery  

Viruses seem like good vectors because they evolved to infect cells. Unfortunately, they don’t always infect the targeted cells, leading to poor biodistribution in heart, muscle, kidney, brain, and other tissues, as well as off-target effects. Payload size is another issue, as AAVs may not accommodate larger genes and/or gene editing tools. 

Another problem is immunogenicity. Patients who have been previously exposed to AAVs (up to 75% of the population) may not be candidates for these therapies, as their immune systems can interfere with dosing. Prior AAV exposure also precludes redosing. Lipid nanoparticles have their own shortcomings, as they can have trouble entering the nucleus, increase inflammation, and show toxicity, again limiting redosing. 

But the most significant barrier may be reimbursement. Approved therapies can cost $2 to $3 million or more for a single treatment. This is no surprise, as delivering genetic payloads with AAVs or LNPs is a complex undertaking. The approach may be sustainable in a rare disease, for which no alternative therapy exists, but health systems and payors could never absorb these costs in common conditions. 

 

Ultrasound’s Advantages 

SonoThera’s technology could help solve these problems. The company is using acoustic energy and microbubbles to selectively target genetic payload delivery to desired cells and tissues, maximizing on-target and minimizing off-target biodistribution.  

“We do an IV infusion of the genetic payload and microbubbles,” said Greenberg. “They flow throughout systemic circulation, but the genetic payload is only delivered where we apply the acoustic energy. Viruses and lipid nanoparticles tend to go to certain organs, but we're not limited that way because we're using a biophysical process.” 

As a result, there are minimal off-target accumulations in the liver, lung, or spleen, which can be common with AAVs and LNPs. Repeat dosing is also feasible because the technology lacks immunogenic viral components. In addition, microbubbles don’t have payload limitations, opening up conditions that require larger genes or complex gene editing tools. 

“We're not limited by the nucleic acid format, so we can deliver DNA, RNA or combinations of the two,” said Greenberg. “More complex therapies, such as CRISPR, may require multiple molecules, and we believe we can accommodate that.”   

For SonoThera, the biggest win may be expanded patient access through improved safety and reduced manufacturing costs. Both microbubbles and ultrasound are FDA approved with excellent safety records. In addition, genetic material and microbubble manufacturing are both well-established, relatively inexpensive processes. 

SonoThera aims to be a fully integrated biotech and is developing this delivery platform and several genetic medicines. In parallel, the company is pursuing biopharma partners that can help support development and eventual commercialization.  

Greenberg believes SonoThera will move its first genetic medicine into the clinic in 2025. Though the indication has not been disclosed, there is enormous unmet need in chronic kidney diseases, hematologic disorders, neurodegenerative diseases, and certain cardiovascular conditions.  

“Once we establish the platform in monogenic diseases, we want to fast track to much more common and complex conditions,” said Greenberg. “Many of these diseases are not currently in scope for gene therapies, however SonoThera’s new delivery technology could completely change the landscape.”