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 young people, retrotransposons are normally held in check by different mechanisms. However, these systems weaken as we age. This allows retrotransposons to reactivate more often. When reactivating they use a reverse transcriptase to copy their genomes and insert them back 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.

Lead candidate TPN-101

TT’s lead candidate is TPN-101 also known as Censavudine. It’s a novel, specific LINE-1 reverse transcriptase inhibitor, to treat neurodegenerative and other diseases of aging in which retrotransposons have been implicated. 

The company states it has follow-on LINE-1 nucleoside inhibitors in early development. It also has Protein Kinase R inhibitors (PKRi). These aim to target pathways activated by LINE-1 that are linked to cognitive impairment.

Progressive Supranuclear Palsy (PSP)

In February of 2024, TT announced the results of a Phase II clinical trial. This was for progressive supranuclear palsy (PSP) patients. In some treatment groups TPN-101 reduced cerebrospinal fluid levels of the neurofilament light chain, a marker of neurodegeneration. Although the study design was complex the effect was not consistent across TPN-101 groups. 

TPN-101 lowered levels of the inflammatory signaling molecule interleukin 6 (IL-6). It also reduced 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). Meanwhile those who had been on placebo from weeks 1 to 24 continued to decline on the drug from weeks 24-48. 

In June, TT announced that the FDA had awarded TPN-101 a Fast Track designation for PSP.

C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia

In July 2024, TT announced the results of a Phase II study. This study focused on TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). These patients have a hexanucleotide repeat expansion in the C9orf72 gene, known as C9-ALS and C9-FTD.

Subjects received one of several doses of TPN-101 under blinded conditions for the first 24 weeks. Then all subjects received open-label TPN-101 for an additional 24 weeks.

In different groups, the drop in breathing ability (vital capacity) for those on the drug was less than half. This was compared to those given a placebo or to what is usual for people at 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 of the Revised ALS Functional Rating Scale (ALSFRS-R) between the TPN-101 and placebo groups. This was true during the first 24 weeks of the placebo-controlled stage. The number of people on the drug for the full 48 weeks dropped less than half of the placebo group. It was about 40% less than what would be expected from historical data.

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 was chosen for the HEALEY ALS trial. This is a Phase II/III adaptive trial for ALS that tests multiple candidates at the same time. The trial is taking place at the Sean M. Healey & AMG Center for ALS. This is at Massachusetts General Hospital (MGH) and is in partnership with the Northeast ALS Consortium (NEALS).

Alzheimer’s Disease

In July 2025, TT announced it received funding from the Alzheimer’s Drug Discovery Foundation (ADDF). This funding will help advance TPN-101 for treating Alzheimer’s disease. A Phase II clinical trial is expected to start by the fourth quarter of 2025.

The company states that AD shares neuropathology in common with other neurodegenerative aging diseases. TPN-101 has shown early signs of effectiveness in these diseases. This includes abnormal tau, which is also found in PSP, and TDP-43. TDP-43 is common in C9-ALS/FTD and in about half of patients with advanced AD.

Cancer

In November 2024, Transposon acquired PrimeFour’s nucleoside analogs to target cancer and neurodegenerative diseases. This collection includes a diverse range of novel nucleoside analogs, each with distinct chemical properties. 

The most promising candidates in the collection aim to create “synthetic lethality” in cancers with certain genetic profiles. This allows for precise targeting of the most vulnerable tumors and reduces side effects.

These compounds may help target cancers with newly identified genetic markers. This is especially true for pancreatic cancer and some other solid tumors, as well as blood cancers. They offer a way for personalized treatment for patients who are most likely to benefit.