Local business works to fill gaps in treatment for people with COVID-19

You could call it a modern David and Goliath story.

NellOne Therapeutics Inc. (NellOne), is a small Knoxville biotech company looking to prove that its new “talented protein” drug can do what Big Pharma’s repurposed drugs have failed to do – heal the injured lungs of many hospitalized people with severe COVID-19 illness and long-haul passengers whose severe symptoms persist for six months or more.

Cymbeline “Bem” Culiat, founder, president and chief scientific officer of NellOne and a former molecular geneticist at Oak Ridge National Laboratory, recently told Friends of ORNL that her company is on an accelerated path toward obtaining approval for the new medicine for humans. clinical trials under the Food and Drug Administration’s Coronavirus Treatment Acceleration Program.

While at ORNL, Culiat discovered the role of the signaling protein NELL1 in directing musculoskeletal and cardiovascular tissue growth and maturation in mice, suggesting that the protein may trigger tissue healing. hard and soft damaged.

Bem Culiat in a NellOne Therapeutics lab in the Fairview building in Knox County.

“A decade of work on various animal and cultured human tissue models by NellOne and other groups around the world is documented in more than 200 publications,” Culiat told his FORNL audience. “This scientific foundation has demonstrated the activity of the NELL1 protein in promoting key processes in tissue healing such as survival under adverse conditions such as inflammation and lack of oxygen, blood vessel formation, control of immune system responses, recruitment of stem cells to injured sites, cell growth and differentiation.

By observing defects in the pro-healing byproduct of a mutated NELL1 gene in a mouse, Bem Culiat discovered at the Oak Ridge National Laboratory the important role of the NELL1 protein in directing the production of healthy tissue for the healing of wounds.

“This activity manifests in major organs such as bones, cartilage, skeletal and cardiac muscles, skin, lungs and brain. It is indeed a very talented protein,” she said.

Culiat described the first time his team, in collaboration with university collaborators, showed that functional tissue formed after a severe injury. They observed that a deep wound in a rat healed when a commercially available sponge-like “scaffold” soaked in a NELL1 protein solution was implanted into the wound cavity.

Cymbeline

“We saw the growth of healthy functional tissue,” Culiat said. “The NELL1 treatment restored new contractile muscles, nerve cells and functioning blood vessels. It improved reconstructive remodeling and there were no adverse immune or toxic responses.

Culiat said his company has made a new patented drug called NV1 (for NELL1 Variant, Protein 1), which is a “recombinant shortened form of the NELL1 protein that is much easier to make as a drug and has a higher great efficacy in soft diseases”. tissues than the longest and most complex protein found in nature.

She added that several studies by her company and independent organizations have shown that NV1 is effective in soft tissue healing.

NellOne Therapeutics is seeking “first-in-class” drug approval for NV1, a therapy that treats a disease problem in a different way because its mechanism of action is new and unique. Big Pharma, she said, has been testing old drugs tailored to target a single molecule partly responsible for the aggressive inflammatory response to the novel coronavirus that damaged the lungs of critically ill COVID-19 patients.

Cymbeline

NellOne has completed and published a proof-of-concept study showing that NV1 increased survival and control of “cytokine storm,” or hyperinflammation, in mice infected with human SARS-CoV-2, the virus that causes COVID-19 disease.

NV1 therapy, Culiat explained, works holistically in that it both reduces inflammation and promotes the regeneration of healthy tissue under low oxygen and other adverse conditions. As a result, damaged sites are replaced with healthy tissues that have normal biological function. She noted that NV1 calibrates multiple switches (like adjusting dimmers) to regulate the entire immune response, whereas most Big Pharma drugs work as a single on-off switch.

The NELL1 signaling protein sends chemical messages that stimulate cells to secrete a mixture of molecules called the extracellular matrix (ECM). The company’s website (https://nell-one.com/) defines the ECM as “a biological glue that orients cells into the correct 3D structure, allowing them to communicate and coordinate their tasks within a tissue or a specific organ.

Bem Culiat in front of NellOne Therapeutics Laboratories in the Fairview Building in Knox County.

According to Culiat, this ECM environment keeps inflammation in check, preventing damaging cytokine storms while immune system cells kill pathogens and shed dead cells; recruits stem cells that form new tissue and blood vessels to deliver oxygen, nutrients and growth factors to support tissue growth and replaces damaged sites with maturing tissue to restore full function biology of damaged areas.

“The ECM environment secreted by cells in response to NELL1 signaling pathways during mammalian fetal development promotes the rapid formation and maturation of new tissues,” Culiat said.

Interestingly, NELL1 is most active during early human development, when true tissue regeneration occurs, or scarless fetal healing.

“As we age we lose signal, so the default mechanism is not the regeneration of healthy tissue but the formation of a scar that lacks the properties and functions of healthy tissue. Scarring is a rapid response to threats to the survival,” she said.

In ORNL’s famous former “Mouse House,” Culiat’s team studied mutant mice that died soon after birth because they lacked a functioning NELL1 gene.

“We saw that their composition and amount of ECM was significantly changed,” she said. “That’s how I knew the NELL1 protein was important in secreting an environment that allowed for healing and regeneration.”

Culiat said NellOne Therapeutics aims to produce medicines that will improve patients’ quality of life and reduce the burden on healthcare systems for patients suffering from acute respiratory distress syndrome (ARDS), particularly ARDS associated with COVID-19, called CARDS. These patients have their lungs so damaged by aggressive, body-damaging inflammation that they are often put on ventilators to get enough oxygen. Their chances of dying are as high as 40%.

“Intravenous administration of NV1 in the hospital could prevent COVID patients from entering intensive care or shorten ventilation time,” Culiat said. “It could be given by IV to recovering COVID long haulers to heal ongoing tissue damage.”

She noted the “staggering economic impact” of lingering COVID-19 illness, which has affected one in seven working-age Americans, according to a Brookings Institute report.

Many have quit their jobs or been unable to work due to lung, heart, brain or kidney damage, exacerbating the current supply chain and labor shortage crises.

NellOne Therapeutics is funded by private, state, and federal sources such as angel investors, the National Science Foundation, and Tennessee Small Business Innovation Research Matching Funds (via LaunchTN). NellOne is led by well-known and highly respected serial entrepreneur Bill Malkes as Managing Director. Malkes and Culiat are supported by an executive and scientific team, each with over 20 years of experience in their respective fields.

As a small company, NellOne multiplied its strength, Culiat said, “by relying on multiple collaborators for drug manufacturing and formulation, safety and efficacy studies, and regulatory approval. Today “Today, the company has two universities and seven private partners with expertise and a track record of success in various aspects of drug development.”