In a Feb. 22 press statement, Denali Therapeutics, based in San Francisco, California, announced it plans to seek Investigational New Drug (IND) approval from the U.S. Food and Drug Administration (FDA) for its enzyme-replacement therapy (ERT) DNL126 designed for addressing the behavioral, cognitive, and physical manifestations of MPS IIIA (Sanfilippo syndrome Type A).
This announcement came ahead of Denali’s presentation of preclinical findings of DNL126 at WORLDSymposium 2023 in Orlando, Florida, last month.
During the presentation, titled “ETV:SGSH, a brain-penetrant enzyme transport vehicle for SGSH, corrects heparan sulfate accumulation, lysosomal lipid storage and inflammation in MPS IIIA mouse brain,” Annie Arguello, PhD, outlined Denali Therapeutic’s approach to ERT to overcome the blood-brain barrier challenge.
Arguello shared the following findings:
- Peripheral administration of ETV:SGSH reduces brain, cerebrospinal fluid (CSF), and liver heparan sulfate levels in a MPS IIIA mouse model, by delivering functional SGSH to the central nervous system (CNS) and periphery.
- ETV:SGSH reduces heparan sulfate levels in neurons, astrocytes, and microglia in the brain parenchyma of MPS IIIA mice and achieves broad distribution of functional enzyme to brain cells.
- Lamp2 staining in the brain of MPS IIIA mice showed ETV:SGSH corrects lysosomal proteins in the brain, suggesting improved lysosome function.
- ETV:SGSH corrects lysosomal lipids in the brain, consistent with improved lysosome function.
- ETV:SGSH corrects neuroinflammation in the brain.
- ETV:SGSH corrects substrate accumulation, lysosomal function and inflammatory markers in a MPS IIIA mouse model.
Dr. Arguello shared the following “conclusions” at the end of her presentation.
You can view the complete presentation regarding DNL126 for Sanfilippo from WORLDSymposium 2023 via Denali’s website at this link.
A photo of the Denali Therapeutics ETV:SGSH Project Team, as shared in the presentation.