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Nervous System Diseases

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Disease Domain	Count

Nervous System Diseases	6
Neoplasms	3
Endocrinology and Metabolic Disease	2

Top 5 Drug Type	Count

Chemical drugs	9

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia worldwide. It is characterized by dysfunction in the U1 small nuclear ribonucleoproteins (snRNPs) complex, which may precede TAU aggregation, enhancing premature polyadenylation, spliceosome dysfunction, and causing cell cycle reentry and death. Thus, we evaluated the effects of a synthetic single‐stranded cDNA, called APT20TTMG, in induced pluripotent stem cells (iPSC) derived neurons from healthy and AD donors and in the Senescence Accelerated Mouse‐Prone 8 (SAMP8) model.MethodFollowing a 7‐day treatment with 5 concentrations of APT20TTMG in iPSC‐derived healthy and AD neurons, mitochondrial activity, glutamate release, and TAU levels were analyzed. The most effective concentration was chosen for the analysis of RNA‐seq differential expression and 3’ untranslated region and coding sequence (UTR/CDS) expression ratios for U1‐70K, SNRP200, MAPT, and APP genes. Levels of U1‐70K, TAU, Aβ, and GFAP were analyzed in 20‐week‐old female SAMP8 mice (Animal Welfare Act, Austria: BGBl. II Nr. 542/2020, BGBl. I Nr. 76/2020, BGBl. I Nr. 86/2018, BGBl. I Nr. 8/2022), treated with 0.3 µg APT20TTMG infused continuously for 42 days (i.c.v.).ResultIn addition to unaffected mitochondrial activity and glutamate release, treatment decreased TAU in AD neurons, with no changes in healthy neurons. Metabolic pathway enrichment and network analysis identified four prominent clusters containing differentially expressed genes (DEGs) associated with pathways like cell cycle, PI3K‐Akt signaling pathway, fatty acid metabolism, MAPK signaling pathway, and steroid biosynthesis. APT20TTMG also corrected target assembly, avoiding premature polyadenylation of all analyzed genes. In vivo, treatment decreased U1‐70K in both cortex and hippocampus, as well as Aβ in cortex, and insoluble pTau in hippocampus. It also reduced gliosis (GFAP) in the cortex of animals.ConclusionAPT20TTMG specifically decreases TAU protein in AD neurons, with a wide safe effect for human brain cells. Its ability to correct the U1 snRNPs dysfunction prevents premature polyadenylation in key genes and leads to a favorable enrichment of DEGs related to pathways deregulated in AD. It also decreases important hallmarks of the disease, in addition to controlling severe astrogliosis. These data evidence the great potential of utilizing APT20TTMG as a disruptive approach for neuronal protection in AD.

Scientific Reports

Effects of the therapeutic correction of U1 snRNP complex on Alzheimer’s disease

Article

Author: Zimmer, Camila G M ; Buée, Luc ; Chua, Xue Ying ; Magdesian, Margaret H ; Poppe, Britt ; Soares, Ericks S ; de Wiart, Adrien Carton ; da Silva, Ronan V ; Leal, Caio Bruno Q S ; Sinatti, Vanessa V C ; Bottos, Rafael M ; Rafii, Michael S

AbstractThe U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer’s disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.

100 Deals associated with Aptah Bio, Inc.

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100 Translational Medicine associated with Aptah Bio, Inc.

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Pipeline

Pipeline Snapshot as of 08 Feb 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

APT-009(Aptah Biosciences)	dry age-related macular degeneration More	Preclinical
APT-002(Aptah Biosciences)	Alzheimer Disease More	Preclinical
APT20TTMG	Alzheimer Disease More	Preclinical
APT-005(Aptah Biosciences)	Amyotrophic Lateral Sclerosis More	Preclinical
APT-008(Aptah Biosciences)	Neoplasms More	Preclinical