NeuExcell Therapeutics is reprogramming glial cells into new neurons in situ to treat major neurodegenerative diseases.
One company, NeuExcell Therapeutics, may have unlocked the method for regenerating neural tissue. The company’s neuroregenerative gene therapy platform is built around transcription factor-based transdifferentiation technology. The platform reprograms endogenous glial cells like astrocytes, which surround neurons and are often reactive after neurons are injured or die, into functional new neurons. While neurons cannot divide to regenerate themselves, glial cells are a renewable source for generating new neurons at the site of injury, and at the scale needed to have a meaningful therapeutic impact.
Most gene therapies are designed to replace a mutant gene. Instead, NeuExcell uses adeno-associated viruses (AAVs) to deliver transcription factors in vivo to the glial cells at the site of injury or neurodegeneration to regenerate new neurons (Fig. 1).
AAVs delivering neural transcription factors such as NeuroD1 to convert an astrocyte into a mature neuron. AAV, adeno-associated virus.
The company was cofounded in 2016 by Gong Chen, a neuroscientist with a keen interest in bringing a new approach directly to patients in a field that has seen little in the way of new, disease-modifying therapies for decades. His original efforts involved transplanting neural stem cells into damaged areas of the brain, but soon found the approach limited.
“I didn’t get a lot of functional neurons out of transplantation,” said Chen, who is also NeuExcell’s founder and Chief Scientific Advisor. “In the past, there was no technology that could regenerate millions—let alone billions—of new neurons in adult mammalian brains. It was unthinkable. But now we are marching toward that goal—an Apollo Project for the neuroregeneration field.”
In 2013, Chen’s group at Pennsylvania State University first reported on an Alzheimer’s disease mouse model that reactive glial cells could be transdifferentiated into functioning new neurons after overexpressing a single neural transcription factor, NeuroD1. They also demonstrated that using AAV to deliver both NeuroD1 and Dlx2, another transcription factor, regenerated GABAergic neurons in a mouse model of Huntington’s disease, significantly improving the life span of the mice. More recently, Chen used NeuroD1 gene therapy to regenerate neurons in a non-human primate model of ischemic stroke, moving one step closer to clinical trials.
“The astrocyte-converted new neurons not only survive well but also project to distant target areas, and form functional circuits as they integrate into the brain network,” said Chen.
After securing exclusive licensing agreements with Penn State, NeuExcell has built upon Chen’s academic work through its two lead programs, NXL-001 in stroke and NXL-002 in Huntington’s disease. The company is preparing for a pre-IND meeting with the U.S. Food and Drug Administration for NXL-001, and on track to apply for INDs for both programs. Chen envisions clinical trials where brain imaging such as MRI is used to identify damaged regions. “It’s a precision medicine approach. Wherever there’s neurons that are lost, you can locally administer the appropriate AAV vectors to regenerate the lost neurons in situ.”
NeuExcell is also developing programs for spinal cord and traumatic brain injuries, plus neurodegenerative disorders including Alzheimer’s disease, Parkinson disease, and amyotrophic lateral sclerosis. Chen thinks the technology is applicable in hundreds of neurological indications. NeuExcell is open to partnerships to accelerate its current product developments as well as to explore areas outside its core business.
The company is pursuing deals with leading gene therapy companies that can complement its technology, said NeuExcell CEO, Ronald Lorijn. “We’re looking for companies that have experience and knowhow with AAV technology in the CNS,” said Lorijn. “And if that company has the experience to help bring us to the next phase faster, that’s a great additional asset.” Lorijn added that NeuExcell is hoping to close its first such partnership by the end of August 2021.
On top of $6.5 million in seed funding, the company has just closed a $12 million pre-A financing round to expand its R&D operations in King of Prussia, Pennsylvania. “Our main focus is on R&D in order to progress our pipeline products as best and fast as we can,” Lorijn said. The company is also planning to close a Series A in 2022 that will support manufacturing and IND-enabling studies and to expand further its presence in China.
