Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 130

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 130
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Case enzyme, leads to Gcase enzyme deficiency resulting in Gaucher disease. Gaucher disease can be associated with debilitating symptoms including a swollen belly from spleen and liver enlargement; bone pain and easily fractured and weak bones; anemia resulting in fatigue. Some people with Gaucher disease have CNS involvement: abnormal eye movements, muscle rigidity, swallowing difficulties, and seizures. There are an estimated 10,000 to 15,000 people with Gaucher disease worldwide (excluding China and India). Approximately 10% of all Parkinson's disease patients are heterozygous carriers of a loss-of-function GBA1 mutation, leading to lysosomal dysfunction which is strongly associated with neuroinflammation/degeneration. There are an estimated 300,000 GBA-PD patients worldwide (excluding China and India). Peripheral enzyme replacement therapy is the current standard of care for Gaucher disease, and no GBA-PD specific treatments currently approved.

DNL111 is composed of an engineered GCase variant for improved potency and fused to TV to replace GCase in all tissues, including the brain by crossing the BBB. In preclinical studies, ETV:Gcase shows improved substrate reduction in brain, liver and serum as compared to Gcase enzyme alone. Further we have engineered the recombinant Gcase enzyme for improved potency. Engineered ETV:GCase may enable highly stable and potent brain-penetrant enzyme replacement therapy for Parkinson’s disease and Gaucher disease.

DNL622 (ETV:IDUA) for MPS I (Hurler syndrome)

Alpha-L-iduronidase (“IDUA”) is as enzyme responsible for degrading heparan and dermatan sulfate in the lysosome. Genetic defects in the gene encoding IDUA result in deficient enzyme activity, leading to MPS I (Hurler syndrome). MPS I is characterized by alterations in the skeleton, heart, respiratory system, and brain and affects approximately 1,500 individuals worldwide. 

DNL622 (ETV:IDUA) is composed of IDUA fused to TV, which is engineered to cross the BBB via RMT into the brain and to enable broad delivery of IDUA into cells and tissues throughout the body with the goal of treating MPS I. DNL622 is currently in the IND-enabling stage of preclinical development.

Oligonucleotide Transport Vehicle (“OTV”) Programs

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Oligonucleotides, such as ASOs and siRNAs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders