Despite significant advances, genetic medicine is still mainly limited to the treatment of rare diseases. Developers strive to expand their reach. The latest addition on Thursday is supported by one of the world’s largest pharmaceutical companies.
The startup Ensoma Therapeutics was created with Series A funding of $ 70 million and an extensive collaboration with Takeda that includes up to five experimental programs. The fundraising was led by venture capital firm 5AM Ventures, as well as half a dozen other investors.
Ensoma’s goal is very ambitious. The company says it will use an unorthodox method of turning genetically modified drugs, which are usually made through a complex, laborious process, into “off the shelf” products. In this way Ensoma wants to develop treatments for common and rare diseases and make them available beyond specialized centers.
“The intent of our therapy is to be able to do this on an outpatient basis, anywhere in a doctor’s office or clinic,” said Paula Soteropoulos, director of Ensoma, an industry veteran who recently ran Akcea Therapeutics.
Paula Soteropoulos, Ensoma Therapeutics
Courtesy Ensoma Therapeutics
In recent years, genetic drugs have shown promise in treating a handful of rare diseases. Two such drugs, Luxturna and Zolgensma, are approved in the United States for eye and neuromuscular diseases, respectively. Others could soon emerge as treatments for rare blood disorders like sickle cell disease and beta thalassemia.
Many of the treatments rely on modified viruses to deliver genetic instructions into the body’s cells – delivery vehicles that come from nature and have both strengths and weaknesses. For example, adeno-associated viruses, or AAVs, are easily infused, have been shown to be safe in clinical tests, and are the backbone of a variety of gene therapies.
However, AAVs can only carry a small amount of genetic cargo and are sometimes turned off by the body’s defenses. The DNA they carry also does not easily integrate into the genome of a target cell, which means that the effects of AAV-based treatment can wear off in cells that divide frequently.
Another commonly used option, lentivirus, integrates and can be used for many different tasks, such as: B. to develop or bypass the defective DNA that causes certain blood diseases.
However, lentiviruses also have limited packaging capacity. And because they are easily integrated into cellular DNA, there is a higher risk of falsely causing cancer-causing mutations, as was the case in a gene therapy trial in France in the early 2000s with a different type of virus. As a result, scientists typically perform such treatments through a strictly controlled process in which cells are first extracted from the body and then precisely modified in a laboratory using lentiviruses.
These “viral vectors” enabled gene therapy to come of age after decades of stop-and-start scientific research. However, its limitations have become increasingly understood, which is why a number of companies have sprung up aiming to improve the technology and expand its impact.
For example, the concept behind Ensoma is to provide a larger and more diverse payload of gene-modifying tools than was possible with comparable viral vectors. The company takes an adenovirus, removes its viral genome, and uses the excess space – about six or seven times the capacity of an AAV – to cram functional genes, or even the means to modify them.
According to Ensoma, its platform can provide genome editing technology such as CRISPR / Cas9 or zinc finger nucleases or instructions for the expression of a gene in cells. “We can bring it all together,” said Kush Parmar, founding CEO and managing partner at 5AM Ventures.
Kush Parmar, Ensoma Therapeutics
Courtesy Ensoma Therapeutics
Preclinical research underlying Ensoma’s approach, published in the Journal of Clinical Investigation in 2019, provided insight into how the approach can be used to develop a treatment for beta thalassemia. In tests on mice, the researchers used a drug to deliver hematopoietic stem cells from the bone marrow into the blood, where they were infected with an infused, genetically engineered adenovirus. The cells then returned to the bone marrow, where they persisted and produced corrected red blood cells.
The study was carried out by an international team of researchers that included André Lieber from the University of Washington, one of Ensoma’s scientific founders. Hans-Peter Kiem from the Fred Hutchinson Cancer Research Center is another.
Ensoma wants to use its method to produce genetic medicines for a variety of rare and common diseases. The hope is that these drugs might be less of a hassle than gene-based treatments that rely on the body’s own cell engineering, like those from Bluebird Bio, CRISPR Therapeutics, and others currently testing for beta thalassemia and sickle cell disease.
Ensoma also expects to be able to avoid the “preconditioning” chemotherapy regimens used by Bluebird and CRISPR in order to prepare patients to receive their cell-based drugs. Transplant specialists, while familiar, can have side effects.
“That sounds really convincing,” said Luk Vandenberghe, director of the Grousbeck gene therapy center at Massachusetts Eye and Ear. Vandenberghe, who is not involved with Ensoma, added that the “complexity” of other approaches “often limits the scope of these therapies, even in the West”.
Ensoma’s method could “be very effective for diseases such as sickle cells” and possibly represent an alternative to the logistically challenging cancer cell therapies that have come onto the market.
Soteropoulos, the company’s chairman, noted that because of the potential convenience benefits, Ensoma may consider using gene therapy to treat infectious or autoimmune diseases.
Before that can happen, however, Ensoma has a lot to prove. Adenoviruses have an eventful past in gene therapy. Although they were among the first delivery tools used in clinical trials, safety concerns – particularly the death of a teenage volunteer two decades ago – limited their use and led to the emergence of AAVs.
“Indeed, innate immunity is the problem that adenovirus therapies must address,” Vandenberghe said. The challenge is to “find a good therapeutic window to avoid the problems that have arisen in the past”. Still, he noted that “the preclinical data in the literature seem encouraging [Ensoma] will find such a window. “
In fact, Parmar said the viruses Ensoma uses are “gutless” and have “extremely low to negligible pre-existing immunity”.
“These are not the adenoviruses from 20 years ago,” he said.
This has to be shown in animal experiments and, if they look positive, in human experiments. Soteropoulos said the “quickest route” to clinical testing is to create endogenous versions of treatments that have shown promise through ex vivo approaches. However, she noted that it is too early to say how far the company is from its initial testing or what diseases it will initially target.
Ensoma could receive up to $ 100 million in upfront and short term payments from Takeda. The startup could also make $ 1.25 billion from the deal later, though that money is not guaranteed and may not materialize.
While Takeda seems like an unusual partner, the Japanese drug maker has taken a giant step towards cell and gene therapy in hopes of improving the current number of treatments. However, the research programs are still at a comparatively early stage.