Transposon Therapeutics, Inc.

Transposon Therapeutics, Inc. (TT) is a clinical-stage biopharmaceutical company developing novel nucleoside reverse transcriptase inhibitors to target retrotransposons, particularly LINE-1. Retrotransposons are the remnants of ancient viral infections that stow away in our genome. In youth, retrotransposons are normally held in check by a variety of mechanisms, but these systems weaken with age, allowing retrotransposons to increasingly reactivate. When they do so, retrotransposons use a reverse transcriptase to replicate their genomes and reinsert them into the host genome. These events cause inflammation and can cause mutations in the host cell. Retrotransposon reactivation is causally implicated in neurodegenerative and other diseases of aging.

TT’s lead candidate is TPN-101 (censavudine), a novel, specific LINE-1 reverse transcriptase inhibitor, to treat neurodegenerative and other diseases of aging in which retrotransposons have been implicated. The company says it has “follow-on [LINE-1nucleoside inhibitors] in preclinical development, as well as Protein Kinase R inhibitors (PKRi) to target pathways activated by LINE-1 and implicated in cognitive impairment.”

Progressive Supranuclear Palsy (PSP)
In February of 2024, TT announced the results of a Phase II clinical trial in progressive supranuclear palsy (PSP) patients, In some treatment arms TPN-101 reduced cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL — a marker of neurodegeneration), although the study design was complex and the effect was not consistent across TPN-101 arms. TPN-101 also lowered levels of the inflammatory signaling molecule interleukin 6 (IL-6) and of osteopontin, a bone signaling molecule whose levels correlate with cognitive impairment in AD. Patients who received TPN-101 for the entire 48-week trial experienced a stabilization of their PSP Rating Scale (PSPRS), while those who had been on placebo from weeks 1 to 24 continued to decline on drug from weeks 24-48. In June, TT announced that FDA had awarded TPN-101 Fast Track designation for PSP.

C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia
In July of 2024, TT announced the results of a Phase II study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS/Lou Gherigs’ disease) and/or frontotemporal dementia (FTD) who carry a hexanucleotide repeat expansion in the C9orf72 gene (C9-ALS and -FTD). Subjects received one of several doses of TPN-101 under blinded conditions for the first 24 weeks, and then all subjects received open-label TPN-101 for an additional 24 weeks.

In different arms, subjects’ decline in vital capacity (a measure of breathing) while on the drug was less than half that in those treated with placebo or than is typical in people in the same stage of ALS. Vital capacity may be a significant surrogate marker, as it correlates with mortality in ALS patients. There was no difference in the decline on the Revised ALS Functional Rating Scale (ALSFRS-R) between the TPN-101 and placebo groups during the initial 24 week placebo-controlled stage, but the decline in people who were on the drug for the full 48 weeks was less than half that of the placebo group, and roughly 40% less than what would be expected based on historical controls.

Subjects treated with TPN-101 also had lower levels of NfL at week 24; the results at week 48 are unclearly described. TT also reported that TPN-101 lowered IL-6, neopterin, and osteopontin.

TT did not separate out effects on subjects better clinically described as FTD in their press release.

In May 2025, TT announced that TPN-101 had been selected for inclusion in HEALEY ALS, a Phase II/III adaptive trial for ALS that will evaluate multiple candidates in parallel. “The trial is being conducted at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and in partnership with the Northeast ALS Consortium (NEALS). Investigators expect to initiate the TPN-101 regimen in the study in the fourth quarter of 2025.”

Alzheimer’s Disease
In July 2025, TT announced that it had obtained funding from the Alzheimer’s Drug Discovery Foundation (ADDF) to advance TPN-101 for the treatment of AD, including a Phase II clinical trial anticipated to begin by Q4 2025. The company notes that AD shares neuropathology in common with other neurodegenerative aging diseases in which TPN-101 has shown preliminary evidence of efficacy, including aberrant tau (shared with PSP) and TDP-43 (endemic in C9-ALS/FTD and in approximately half of advancing AD patients).

Cancer
In November 2024, Transposon acquired a portfolio of novel nucleoside analogs from PrimeFour Therapeutics that are claimed to cause synthetic lethality in cancers with specific genetic signatures, offering the potential of highly specific targeting of a subset of cancers while reducing toxicity.