DNL628 is an antisense oligonucleotide (ASO) targeting tau (MAPT) mRNA, developed by Denali Therapeutics using the company's proprietary Oligonucleotide Trafficking Vehicle (OTV) technology for enhanced blood-brain barrier (BBB) penetration. It is currently in Phase 1b clinical development for early Alzheimer's disease under NCT07328451.
| Attribute |
Details |
| NCT Number |
NCT07328451 |
| Phase |
Phase 1b |
| Status |
Recruiting (as of 2026) |
| Sponsor |
Denali Therapeutics |
| Indication |
Early Alzheimer's disease (MCI due to AD or mild AD dementia) |
| Mechanism |
Tau ASO — reduces MAPT mRNA and protein |
| Delivery |
OTV (Oligonucleotide Trafficking Vehicle) for BBB penetration |
| Route |
Intrathecal (IT) injection |
| Enrollment |
68 participants (estimated) |
DNL628 is designed to reduce tau protein production through an antisense mechanism:
- Target: MAPT mRNA — the gene encoding the Tau protein
- ASO design: Single-stranded oligonucleotide that binds complementary sequence in MAPT pre-mRNA, recruiting RNase H for catalytic degradation of the target mRNA
- Downstream effects: Reduced intracellular tau leads to less extracellular tau release, decreased tau aggregation, and reduced spread of pathological tau
- BBB penetration: The OTV technology is designed to cross the blood-brain barrier and distribute to CNS neurons, enabling a potential peripheral (IV) delivery approach for ASOs that traditionally require intrathecal administration
Denali's OTV platform is a key differentiator:
- Transferrin receptor (TfR) binding: OTV molecules are designed to engage TfR on the luminal side of brain endothelial cells, facilitating transcytosis across the BBB
- CNS neuron targeting: After transcytosis, OTV-ASOs distribute widely in neurons throughout the brain
- Reduced dosing frequency: Enhanced CNS exposure may enable less frequent dosing compared to conventional ASOs
- Applies to multiple CNS programs: Denali's LRRK2 ASO (DNL351) and other programs also use OTV delivery
Tau pathology (neurofibrillary tangles) strongly correlates with cognitive decline in AD, even more than amyloid burden in many studies:
- Braak staging of NFT pathology correlates with clinical severity
- Tau PET imaging shows patterns of spread that mirror clinical progression
- Reducing tau has been shown to improve cognition in multiple animal models
- Two other tau ASO programs (Ionis/BIIB080 for AD, NIO752 for PSP) have shown target engagement in humans
| Program |
Company |
Indication |
Delivery |
Stage |
| DNL628 |
Denali |
Early AD |
OTV |
Phase 1 |
| BIIB080 (IONIS-MAPT) |
Ionis/Biogen |
AD/PSP |
Conventional IT |
Phase 1/2 |
| NIO752 |
Novartis |
PSP |
Conventional IT |
Phase 2 |
| APO001 |
Prevail Therapeutics |
AD/PD |
AAV gene therapy |
Preclinical |
DNL628's key differentiation is the OTV delivery technology, which may provide superior CNS exposure and distribution compared to conventional ASOs.
Based on the NCT07328451 protocol, this is a multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose (MAD) study:
- Part A (if applicable): Single ascending dose cohorts
- Part B: Multiple ascending dose (MAD) cohorts receiving multiple doses of DNL628
- Primary objectives: Safety and tolerability of DNL628
- Secondary objectives: Pharmacokinetics in plasma and CSF, pharmacodynamics (CSF biomarkers including total tau and p-tau181)
- Safety: Adverse events, serious adverse events, laboratory abnormalities, ECG changes
- Pharmacokinetics: CSF and plasma concentrations of DNL628 over time
- Pharmacodynamics: Change from baseline in CSF biomarkers
- Cognitive: Change from baseline on ADAS-Cog13 and CDR-SB at 3, 6, 12 months
- Inclusion: Diagnosis of probable AD dementia (NIA-AA 2011 criteria), amyloid positivity confirmed at screening, Clinical Dementia Rating (CDR) global score of 0.5 or 1, MMSE score of 20-30, BMI 18-32 kg/m2, body weight ≥45 kg
- Amyloid confirmation: Confirmed amyloid pathology via PET or CSF (centiloid > 20)
- Exclusion: Other neurodegenerative conditions, significant psychiatric conditions, other causes of cognitive impairment, prior anti-amyloid or anti-tau immunotherapy, prior gene therapy exposure
DNL628 trials incorporate a comprehensive biomarker panel:
| Biomarker |
Target |
Utility |
| CSF total tau |
Target engagement |
Reduced after ASO treatment (dose-dependent) |
| CSF p-tau181 |
Disease modification |
Tracking tau phosphorylation reduction |
| CSF p-tau217 |
Disease modification |
Highly specific for AD tauopathy |
| CSF NfL |
Neuroaxonal injury |
Monitoring for off-target effects |
| Tau PET (MK-6240) |
Disease spread |
Imaging tau burden changes at higher doses |
DNL628 is part of Denali's broader CNS oligonucleotide strategy:
- DNL351 (LRRK2 ASO): Phase 2 in Parkinson's disease for G2019S LRRK2 mutation carriers
- DNL692 (RIPK1 ASO): Preclinical for ALS and Frontotemporal Dementia
- Partnered with Biogen: Collaboration on tau ASO programs (BIIB080/IONIS-MAPT) includes options on Denali's tau ASO pipeline
Denali Therapeutics is a precision neuroscience company founded by former Genentech executives, with a focus on developability and delivery technologies for large molecules and oligonucleotides in neurodegeneration.