Our Pipeline

LRRK2 is the most common genetic risk factor for Parkinson's disease, and is involved in maintaining a healthy cellular environment by regulating lysosomal function.  Increased levels of LRRK2 lead to lysosomal dysfunction, which contributes to neurodegeneration and the formation of Lewy bodies, a central pathology of Parkinson's disease. DNL151 is a potent, selective and brain-penetrant small molecule inhibitor of LRRK2 and is Denali's clinical candidate for Parkinson's disease.

The Iduronate 2-sulfatase enzyme (IDS) is responsible for breaking down heparan and dermatan sulfates in the lysosome and thereby maintining celluar homeostasis.  Genetic defects in IDS lead to a deficiency in IDS and cause Hunter Syndrome (or MPS II), which is characterized by abnormalities in the skeleton, heart, respiratory system, and the brain. DNL310 (or ETV:IDS) is a recombinant IDS enzyme engineered to cross the blood-brain barrier and to replace the IDS enzyme and treat neuropathic and systemic forms of the disease.

Progranulin (PGRN) is required for maintaining normal lysosomal function, and loss of PGRN results in the dysregulation of multiple lysosomal enzymes. Genetic mutations that result in loss of PGRN function are sufficient to cause Frontotemporal Dementia (FTD). DNL593 is a recombinant PGRN protein engineered to cross the blood-brain barrier and enter multiple cell types in brain to treat patients with FTD resulting from PGRN deficiency.

N-sulfoglucosamine sulfohydrolase (SGSH) is an enzyme responsible for degrading heparan sulfates in the lysosome.  Genetic defects that result in a reduction in the lysosomal activity of SGSH cause Sanfilippo syndrome A (or MPS IIIA).  Sanfilippo syndrome A is characterized by elevated levels of glysosoaminoglycans, recurrant infection, and developmental and behavioral abnormalities. ETV:SGSH is a recombinant SGSH enzyme engineered to cross the blood-brain barrier, replace the SGSH enzyme and treat neuropathic and systemic forms of the Sanfilippo syndrome A.

Glucocerebrosidase (GCase) is an enzyme responsible for degrading glucosylceramide within lysosomes. Genetic variants in the glucocerebrosidase gene are the most common genetic risk factor for developing Parkinson's disease and result in reduced lysosomal GCase activity. Reduced GCase activity as a result of mutations in the gene GBA leads to lysosomal dysfunction, which contributes to neurodegeneration and the formation of Lewy bodies, a central pathology of Parkinson's disease. ETV:GCase is a recombinant GCase enzyme engineered to cross the blood-brain barrier and increase GCase activity in the brain to treat Parkinson's disease.

Arylsulfatase A (ARSA) is an enzyme responsible for breaking down sulfatides within lysosomes. Genetic variants in ARSA result in a reduction of lysosomal ARSA enzymatic activity and cause Metachromatic Leukodystrophy (MLD). MLD is characterized by an accumulation of sulfatides leading to neuronal degradation resulting in progressive cognitive and motor decline. ETV:ARSA is a recombinant ARSA enzyme engineered to cross the blood-brain barrier and to replace ARSA to treat neuropathic and systemic manifestations of the disease.

Alpha-N-acetylglucosaminidase (NAGLU) is an enzyme responsible for degrading heparan sulfate in the lysosome. Genetic defects in NAGLU result in a reduction or absence of lysosomal NAGLU activity and cause Sanfilippo syndrome B (or MPS IIIB), which is characterized by recurrent infection and developmental and behavioral abnormalities. ETV:NAGLU is a recombinant NAGLU enzyme engineered to cross the blood-brain barrier and replace NAGLU to treat neuropathic and systemic manifestations of the disease.

Alpha-L-iduronidase (IDUA) is an enzyme responsible for degrading heparan and dermatan sulfate in the lysosome. Genetic defects in IDUA result in a reduction or absence of lysosomal IDUA activity and cause Hurler syndrome (or MPS I), which is characterized by alterations in the skeleton, heart, respiratory system, and the brain. ETV:IDUA is a recombinant IDUA enzyme engineered to cross the blood-brain barrier, to replace IDUA, and to treat the neuropathic and systemic forms of the disease.

Acid-α-glucosidase (GAA) is an enzyme responsible for degrading glycogen in the lysosome. Genetic variants in GAA that result in a reduction in the lysosomal activity of GAA cause Pompe disease and can lead to an accumulation of lysosomal glycogen in peripheral tissues, including muscle, and in the brain. ETV:GAA is a recombinant GAA enzyme engineered to cross the blood-brain barrier, replace the GAA enzyme, and treat the neuropathic and system aspects of Pompe disease.

OTV:LF3 is an undisclosed oligonucleotide transport vehicle program that utilizes Denali's proprietary BBB platform technology to deliver a therapeutic molecule to the brain.