A Phase 2a Study of TPN-101 in Patients With Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated With Hexanucleotide Repeat Expansion in the C9orf72 Gene (C9ORF72 ALS/FTD)

This is a Phase 2a study to assess the the safety and tolerability of TPN-101 in patients with Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated with Hexanucleotide Repeat Expansion in the C9orf72 gene (C9ORF72 ALS/FTD).

开始日期2021-10-01

申办/合作机构

Transposon Therapeutics, Inc.初创企业

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项与 Transposon Therapeutics, Inc. 相关的文献（医药）

2023-07-18·Genome medicine

Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy.

Article

作者: Sturm, Virginia E ; Seeley, William W ; Geier, Ethan G ; Bonham, Luke W ; Boxer, Adam L ; Yokoyama, Jennifer S ; Johnson, Taylor P ; Lee, Suzee E ; Rosen, Howard J ; Warly Solsberg, Caroline ; Miller, Bruce L ; Sirkis, Daniel W ; Rankin, Katherine P

BACKGROUND:

Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system.

METHODS:

To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau (n = 8), and healthy non-carrier controls (n = 8). Primary findings from our scRNA-seq analyses were confirmed and extended via flow cytometry, droplet digital (dd)PCR, and secondary analyses of publicly available transcriptomics datasets.

RESULTS:

Analysis of ~ 181,000 individual PBMC transcriptomes demonstrated striking differential expression in monocytes and natural killer (NK) cells in MAPT pathogenic variant carriers. In particular, we observed a marked reduction in the expression of CX3CR1-the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models-in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia but with unclear function in peripheral monocytes. We confirmed the reduction in nonclassical monocytes by flow cytometry and the differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using ddPCR.

CONCLUSIONS:

Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

bioRxiv : the preprint server for biology

Expansion of highly interferon-responsive T cells in early-onset Alzheimer’s disease

作者: Johnson, Taylor P ; Rabinovici, Gil D ; Oddi, Alexis P ; Yokoyama, Jennifer S ; Solsberg, Caroline Warly ; Geier, Ethan G ; Miller, Bruce L ; Sirkis, Daniel W ; Bonham, Luke W

Abstract:

INTRODUCTION:

Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer’s disease (EOAD).

METHODS:

We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls.

RESULTS:

We analyzed ~182,000 PBMCs by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhiT cells in EOAD. We isolated CD4 T cells from additional EOAD cases and confirmed increased expression of ISAGhimarker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes.

DISCUSSION:

ISAGhiT cells, apparently primed for antiviral activity, are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.

项与 Transposon Therapeutics, Inc. 相关的新闻（医药）

2024-11-21

·PRNewswire

Transposon Therapeutics Strengthens and Expands Development Pipeline with the Acquisition of a Portfolio of Novel Nucleoside Analogs for Oncology

Portfolio of nucleoside chemotherapeutics for the targeted treatment of pancreatic cancer, certain other solid tumors and hematologic cancers Builds upon leadership position in developing best-in-class, late-stage nucleoside reverse transcriptase inhibitors for neurodegenerative and autoimmune diseases SAN DIEGO, Nov. 21, 2024 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases, today announced the acquisition of a portfolio of novel nucleoside analogs from PrimeFour Therapeutics, Inc., a biotechnology company focused on cancer chemotherapeutic agents. The portfolio of novel nucleosides consists of a chemically diverse library of unique analogs. The most advanced lead compounds are nucleosides that cause "synthetic lethality" in cancers characterized by distinct tumor-defined genetic signatures, allowing them to be precisely targeted to the most susceptible cancers with reduced toxicity. These compounds can be targeted towards cancers with newly discovered genetic biomarkers that are present in pancreatic and certain other solid tumors as well as in hematologic cancers, allowing for personalized therapy in those patients most likely to respond to treatment. "This transaction allows us to build upon our leadership in developing first-in-class and best-in-class nucleoside reverse transcriptase inhibitors for neurodegenerative and autoimmune diseases, including ALS, PSP and Alzheimer's disease. We are excited to expand our pipeline to include this portfolio of potent nucleoside chemotherapeutics with significant therapeutic potential against a variety of cancers," said Eckard Weber, M.D., founder and Chief Innovation Officer of Transposon. "We look forward to advancing the lead compounds into preclinical development to target DNA-damage repair deficient cancers, such as pancreatic and colorectal cancers." About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel nucleoside reverse transcriptase inhibitors for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. Transposon is advancing TPN-101 into Phase 3 registration studies for the treatment amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP), and a Phase 2 proof-of-concept study in Alzheimer's disease. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. About PrimeFour PrimeFour discovered and developed a class of novel nucleoside analogs that are selectively incorporated into cancer cells with biomarker-identifiable DNA damage repair deficiencies and that, once incorporated into some cancer cells, cause irreversible DNA damage and cancer cell death. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 [email protected] SOURCE Transposon Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

并购临床2期临床3期

2024-11-06

·PRNewswire

Transposon to Present Results from Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related ALS/FTD at the 7th Annual ALS ONE Research Symposium

Treatment with TPN-101 showed clinical benefits on key clinical outcome measures, including the Revised ALS Functional Rating Scale (ALSFRS-R) and Slow Vital Capacity (SVC) TPN-101 also had lowering effects on key biomarkers of neurodegeneration and neuroinflammation, including neurofilament light chain (NfL) and interleukin 6 (IL-6) SAN DIEGO, Nov. 6, 2024 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease, today announced that results from its Phase 2 study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD) will be presented at the 7th Annual ALS ONE Research Symposium. The symposium will take place virtually on November 13-15, 2024. Presentation details For more information, please visit the ALS ONE Research Symposium website. About the Phase 2 Study in C9orf72-related ALS/FTD The Phase 2 study in patients with C9orf72-related ALS/FTD was a multi-center, randomized, double-blind, placebo-controlled parallel-group, two-arm study with an open-label treatment period. Participants (n=42) were randomized 3:2 to receive daily doses of 400 mg of TPN-101 or placebo. The study included a six-week screening period, a 24-week double-blind treatment period, a 24-week open-label treatment period, and a follow-up visit four weeks post-treatment. Further information on the study can be accessed at ClinicalTrials.gov. About TPN-101 TPN-101 specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication. LINE-1 elements are a class of retrotransposable elements that in humans are uniquely capable of replicating and moving to new locations within the genome. When this process becomes dysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 cDNA, triggering innate immune responses that contribute to neurodegenerative, neuroinflammatory, and aging-related disease pathology. About ALS and FTD ALS is a neurodegenerative disease characterized by progressive muscle weakness, and loss of ability to speak, eat, move or breathe. FTD is a progressive frontal/temporal cortex disease associated with behavior and personality changes, emotional problems, and difficulty walking, communicating, or working. A C9orf72 hexanucleotide repeat mutation accounts for 10-15% of both disorders. With onset commonly in middle age or earlier, patients with ALS have a mean survival of two to three years. Patients with FTD have a mean survival of nine years. About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 [email protected] SOURCE Transposon Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床结果临床2期寡核苷酸

2024-10-09

·PRNewswire

Transposon to Present Results from Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related ALS/FTD at the 2024 Annual NEALS Meeting

TPN-101 had lowering effects on key biomarkers of neurodegeneration and neuroinflammation, including neurofilament light chain (NfL) and interleukin 6 (IL-6) Treatment with TPN-101 also showed clinical benefits on the Revised ALS Functional Rating Scale (ALSFRS-R) and Vital Capacity, key clinical outcome measures for ALS SAN DIEGO, Oct. 9, 2024 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease, today announced that results from its Phase 2 study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD) have been accepted for both oral and poster presentation at the 2024 Annual Northeastern Amyotrophic Lateral Sclerosis Consortium (NEALS) Meeting. The hybrid meeting will take place October 21-24, 2024, in Clearwater, Florida, and virtually. "Given the effects of TPN-101 on key biomarkers of neurodegeneration and neuroinflammation, including NfL and IL-6, and clinical outcome measures of disease progression and respiratory function in patients with C9orf72-related ALS, we are very pleased these data were accepted for presentation at NEALS," said Andrew Satlin, M.D., Chief Medical Officer at Transposon. "Based on these promising results, we are advancing TPN-101 into a Phase 3 registration study for the treatment of C9orf72-related ALS, while also continuing to develop TPN-101 for other neurodegenerative diseases." Oral presentation details The poster will also be on view during Poster Session 2 on Wednesday, October 23, 2024, from 4:00 to 6:00 pm EDT. For more information, please visit the 2024 Annual NEALS Meeting website. About the Phase 2 Study in C9orf72-related ALS/FTD The Phase 2 study in patients with C9orf72-related ALS/FTD was a multi-center, randomized, double-blind, placebo-controlled parallel-group, two-arm study with an open-label treatment period. Participants (n=42) were randomized 3:2 to receive daily doses of 400 mg of TPN-101 or placebo. The study included a six-week screening period, a 24-week double-blind treatment period, a 24-week open-label treatment period, and a follow-up visit four weeks post-treatment. Further information on the study can be accessed at ClinicalTrials.gov. About TPN-101 TPN-101 specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication. LINE-1 elements are a class of retrotransposable elements that in humans are uniquely capable of replicating and moving to new locations within the genome. When this process becomes dysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 cDNA, triggering innate immune responses that contribute to neurodegenerative, neuroinflammatory, and aging-related disease pathology. About ALS and FTD ALS is a neurodegenerative disease characterized by progressive muscle weakness, and loss of ability to speak, eat, move or breathe. FTD is a progressive frontal/temporal cortex disease associated with behavior and personality changes, emotional problems, and difficulty walking, communicating, or working. A C9orf72 hexanucleotide repeat mutation accounts for 10-15% of both disorders. With onset commonly in middle age or earlier, patients with ALS have a mean survival of two to three years. Patients with FTD have a mean survival of nine years. About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 [email protected] SOURCE Transposon Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床结果临床2期寡核苷酸

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