Trial testing new ALS gene therapy starts dosing patients in Australia
Main goal is safety, but study also looking for signs of CTx1000's effectiveness
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- A new gene therapy, Celosia's CTx1000, is now being tested for ALS in a small clinical trial in Australia.
- The one-time treatment targets toxic TDP-43 protein clumps, a key driver of most cases of ALS.
- The newly launched trial will focus on the therapy's safety and potential effectiveness over three years.
The first patient has been dosed in a small clinical trial in Australia that’s testing CTx1000, Celosia Therapeutics’ experimental gene therapy, in people with amyotrophic lateral sclerosis (ALS).
The one-time treatment is designed to reduce toxic buildups of the TDP-43 protein, which are believed to contribute to nerve cell damage in ALS.
The Phase 1b trial, dubbed KOANEWA (NCT07401121), is expected to enroll about 15 adults at the Macquarie University Hospital in Sydney. All will receive a single dose of CTx1000, which will be delivered directly into the spinal fluid at the base of the brain.
The trial’s main goal is to evaluate the treatment’s safety and tolerability, but researchers will also be looking out for signs of efficacy over three years, according to a press release from the developer.
“The initiation of dosing in the KOANEWA study marks an important milestone for Celosia and, most importantly, for the ALS community,” said Kathryn Sunn, PhD, Celosia’s CEO . “Treating the first patient begins the clinical evaluation of this genetic medicine and represents a meaningful step toward a potential disease‑modifying therapy for people living with ALS.“
ALS is caused by the progressive loss of motor neurons, the nerve cells that control voluntary movement. Exactly what causes these cells to become dysfunctional and die is not fully understood, but abnormal TDP-43 protein clumps — seen in about 97% of all ALS patients — are believed to be a driver of the disease.
Gene therapy candidate targets TDP-43 protein clumps in ALS
Normally, this protein is found in the nucleus, the cellular compartment where DNA is stored. There, it helps process molecules that carry genetic instructions to make proteins.
In ALS, however, TDP-43 becomes abnormal and prone to form toxic clumps outside the nucleus, preventing it from performing its normal function.
Researchers at Macquarie previously found that abnormal versions of TDP-43 seen in ALS are able to stick to another protein, one called 14-3-3, which binds much less strongly to the normal version of TDP-43. The team also identified the exact part of the 14-3-3 protein that binds abnormal TDP-43.
CTx1000 works by delivering to cells a gene that provides instructions to produce that portion of 14-3-3 fused to a degradation tag— essentially creating a molecule that can bind to abnormal TDP-43 and mark it for destruction by the cell.
The gene is delivered using an adeno-associated virus serotype 9 (AAV9), a type of viral vector widely used in gene therapies for neurological disorders due to its ability to efficiently deliver genes to nerve cells without causing illness. According to the company, the treatment has the potential to be disease-modifying.
This trial, the first in humans, is enrolling people with ALS whose first symptoms started within the last two years. Eligible participants will be receiving stable doses of standard ALS treatments. The trial has an open-label design, meaning all patients will be treated and there will be no control group.
This study is a major milestone for our research program, advancing a novel disease-modifying therapeutic strategy into the clinic that, for the first time, directly targets a fundamental disease mechanism in ALS — the [disease-driving] accumulation of TDP-43.
CTx1000 is delivered through an injection into the cisterna magna, a large pocket of spinal fluid located at the base of the brain. This is a minimally invasive delivery method that is sometimes used to deliver AAV-based gene therapies directly to the brain.
The trial’s main goal is to evaluate the treatment’s safety and tolerability for up to one year. Secondary measures include long-term assessment of safety and tolerability, pharmacological properties, and changes in ALS Functional Rating Scale Revised (ALSFRS-R) for up to three years.
“This study is a major milestone for our research program, advancing a novel disease-modifying therapeutic strategy into the clinic that, for the first time, directly targets a fundamental disease mechanism in ALS — the pathological [abnormal and potentially disease-driving] accumulation of TDP-43,” said Lars Ittner, MD, Celosia’s founder and chief scientific and medical officer.
According to Ittner, “evaluating CTx1000 in people living with ALS will enable us to assess the safety of this approach while also exploring its potential to therapeutically address one of the key drivers of disease.”
