The company is planning to apply for its first in-human clinical trial with the U.S. Food and Drug Administration.
The gene therapy uses a novel viral vector to deliver a fully functional heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT), the gene mutated in Sanfilippo syndrome type C patients. People with HGSNAT mutations lack an enzyme essential for the proper degradation of large sugar molecules called glycosaminoglycans.
This “gene therapy demonstrated preclinical evidence from behavioral and cognitive tests which provide an expectation of direct clinical benefit,” Brian Bigger, PhD, a professor of cell and gene therapy at the University of Manchester, said in a press release.
“The vector we are using has an established safety profile and is in widespread use in treating conditions of neurological origin. It is our expectation that this will translate into a successful treatment for this disease,” added Bigger, who is also the lead author of a recent study on the gene therapy.
Gene therapies are viewed as one of the most exciting potential therapies for diseases with a genetic cause. Most gene therapies rely on the use of inactivated viruses, namely adenoviruses (AAV), which, upon infection, can introduce the gene of interest into a target cell.
However, while AAV-mediated gene therapies have successfully targeted the eye, muscle, and liver, their effectiveness for neurological diseases is still limited. One such limitation is the difficulties in getting these therapies to reach nerve cells in the brain, which is protected by the blood-brain barrier, a semi-permeable membrane that “shields” it from the outside environment.
Researchers at the University of Manchester and King’s College London developed a new AAV vector that can target cells in the central nervous system, which includes both the brain and the spinal cord.
This vector, called AAV-TT, was injected into the brains of newborn mice and tracked with a fluorescent marker. Results showed that AAV-TT could efficiently reach and distribute throughout the central nervous system.
Researchers then tested the ability of the AAV-TT vector to deliver a functional, human HGSNAT gene into a mouse model of Sanfilippo syndrome type C.
After four months of intracranial injections of the gene therapy, they observed that the AAV-TT-HGSNAT vector corrected animals’ behavior compared with control vectors that were also “loaded” with the HGSNAT gene. Specifically, they measured the mice’s performance in the open field test, which measures an animal’s ability to explore, assessing working and spatial memory.
At six months after vector delivery, while both AAV-TT- HGSNAT vector and control vectors increased the levels of the HGSNAT protein in the brain, they were higher in animals treated with the AAV-TT vector, which was also able to lower neuroinflammation in the animals’ brain cortex.
Findings were published in the study, “A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency” in the journal Brain.
The gene therapy has received orphan designation — which aims to encourage the development of therapies for rare and serious diseases — from the European Medicines Agency.
“We are excited about the potential of this gene therapy. Phoenix Nest Inc. has an orphan designation for this treatment from the EMA and is currently submitting this designation to the FDA along with the Pre-IND [investigational new drug application]. We are also starting vector manufacturing in preparation for a clinical trial in the very near future,” said Jill Wood, co-founder and chief financial officer of Phoenix Nest.
“Phoenix Nest is in great admiration of the parents of children affected by Sanfilippo Syndrome. These families have taken a disease with no hope of survival to the brink of a clinical trial. These are the heroes that deserve all the credit for identifying and funding leading academics and inspiring the scientists to create a drug for this insidious disease. If not for my child, then for the next generation, no parent should have to watch their child slowly die of a genetic syndrome that can be treated,” Wood added.