Genetic Pathway Potential
Advances in the genetics, pathology and cell biology underlying chronic neurodegenerative disease have identified pathways that trigger neurodegeneration and contribute to disease onset and progression. Denali is applying deep scientific and drug development expertise to fully harvest the potential of these pathways and discover effective molecular therapeutics.
Each program is addressing a target or pathway that is genetically validated to cause or increase the risk for neurodegenerative diseases.
Degenogenes
Rapid progress in identifying human genetic risk associated with neurodegenerative disease has revealed numerous genes involved in neurodegeneration. Degenogenes are genes that when mutated cause, or are major risk factors for, neurodegenerative disease. These degenogenes highlight important disease pathways for therapeutic discovery, including lysosomal function, glial biology and cellular homeostasis.
Lysosomal Function
The lysosomal system, the disposal and recycling compartment of the cell, is involved in the digestion and processing of proteins and lipids in brain cells. Dysfunction of the lysosomal system is associated with several neurodegenerative disorders, including Parkinson’s disease and neurodegeneration in the context of lysosomal storage diseases, or LSDs. Therapeutics designed to correct lysosomal dysfunction are a promising approach to treat neurodegeneration.
Drug Candidates
Parkinson's
DNL151
Program Target
LRRK2
Development Stage
Early Clinical
MPS II (Hunter Syndrome)
DNL310 (ETV:IDS)
Program Target
Iduronate 2-sulfatase
Development Stage
Early Clinical
Frontotemporal Dementia
DNL593 (PTV:PGRN)
Program Target
Progranulin
Development Stage
IND-Enabling
Parkinson's DLB MSA
ATV:aSyn
Program Target
Alpha-Synuclein
Development Stage
Drug Discovery
MPS IIIA (Sanfilippo Syndrome)
DNL126 (ETV:SGSH)
Program Target
Sulfamidase
Development Stage
IND-Enabling
Parkinson's, Gaucher disease
ETV:GCase
Program Target
GCase
Development Stage
Drug Discovery
Parkinson's
AAV:LF2
Program Target
Undisclosed
Development Stage
Drug Discovery
Glial Biology
The human brain contains several types of glial cells. These cells serve various functions in the brain, including supporting neuronal health, pruning neuronal synapses, and providing immune surveillance and response. Genetic and pathological data suggest that glial dysfunction significantly contributes to neurodegenerative disease. Correcting glial dysfunction represents an attractive therapeutic strategy.
Drug Candidates
ALS Alzheimer's MS
DNL788
Program Target
RIPK1
Development Stage
Early Clinical
Alzheimer's
DNL919 (ATV:TREM2)
Program Target
TREM2
Development Stage
IND-Enabling
ALS
GB1
Program Target
Undisclosed
Development Stage
Drug Discovery
Cellular Homeostasis
Many degenogenes directly alter cellular homeostasis in the brain. Specifically, defects in protein, RNA or metabolic homeostasis leads to the death of neurons and dysfunction of the nervous system. This includes spreading of protein aggregates resulting in proteinopathy in Alzheimer’s and Parkinson’s diseases, and the aggregation of RNA binding proteins disrupting cellular stress response in ALS and Alzheimer’s disease. Therapies that correct defects in cellular homeostasis have the potential to halt neurodegeneration.
Drug Candidates
ALS FTD
DNL343
Program Target
EIF2B
Development Stage
Early Clinical
Alzheimer's
ATV:Tau
Program Target
Tau
Development Stage
Drug Discovery
Alzheimer's
ATV:Abeta
Program Target
Abeta
Development Stage
Drug Discovery
ALS Parkinson's
CH1
Program Target
Undisclosed
Development Stage
Drug Discovery