Science Science

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.

Genentic Pathway

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.

Lysosomal Function

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.

Glial Biology

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.

Cellular Homeostasis

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