HDSA 2026: Huntington’s gene therapy may move to clinical trials

Latus Bio plans to submit an application with the U.S. Food and Drug Administration (FDA) to move LTS-201, a one-time gene therapy for Huntington’s disease, into clinical trials.

The application, which the company expects to file in the current quarter, leverages promising results in Huntington’s animal models showing the treatment reached brain regions affected by the disease and slowed CAG repeat expansion, a genetic process linked to disease onset and progression. The FDA has 30 days after submission to review the data, and if the agency approves, the company will start a first-in-human trial of LTS-201 in the U.S.

“We’re very excited that LTS-201 is poised to become the very first therapy in the clinic to test this hypothesis that the expansion of CAG [repeats] over time could be playing a role in Huntington’s disease,” George Yohrling, PhD, Latus’ executive director of development, said in at the 41st Huntington’s Disease Society of America (HDSA) annual convention, held last week in Phoenix, in a talk titled, “LTS-201: A Novel Gene Therapy Approach for Huntington’s Disease.”

The preclinical results are available in the form of a non-peer-reviewed article titled “Computational modeling and preclinical validation support targeting somatic instability for Huntington’s disease treatment.”

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Slowing disease via protein destruction

Huntington’s is caused by excessive repetition of a sequence of three building blocks of DNA — cytosine (C), adenine (A), and guanine (G) — in the HTT gene, leading to the production of an abnormally long huntingtin protein that forms toxic clumps in nerve cells. The disease particularly leads to the loss of medium spiny neurons (MSNs) in a deep brain region called the striatum.

CAG repeat expansions are unstable and can progressively lengthen over a person’s lifetime through a process called somatic CAG repeat expansion. These somatic expansions are believed to contribute to disease onset and progression, with longer CAG repeats linked to earlier onset and more severe disease.

One of the proteins involved in somatic CAG expansion is MSH3, a DNA-repair protein. “Human genetic studies found that there are [Huntington’s patients] naturally making less MSH3 … and those patients have a later onset or slower progression of Huntington’s disease,” Yohrling said. “That led to a simple question: could lower MSH3 slow the disease? And that’s the idea around LST-201.”

LTS-201 uses a modified, harmless adeno-associated virus (AAV) to deliver to cells a small piece of genetic material, called microRNA, that binds MSH3 gene’s messenger RNA — an intermediary molecule that guides protein production — targeting it for destruction.

This is expected to lower the production of MSH3 protein, slowing somatic CAG expansion and slowing or halting Huntington’s progression.

Unlike other experimental therapies currently in development, which target “huntingtin directly,” Yohrling said, LTS-201 is designed to “lower MSH3 in brain cells with … the goal of slowing CAG expansion.”

LTS-201 is administered directly into the globus pallidus, a deep brain region connected to the striatum, via an MRI-guided surgical procedure under anesthesia. It’s a one-time approach that allows the delivery of LTS-201 where it’s needed while limiting exposure to the rest of the body.

The Latus-developed AAV used in the gene therapy, called AAV-DB-3, has been shown to effectively deliver its cargo to MSNs and brain regions mostly affected by Huntington’s.

When injected into the globus pallidus in healthy nonhuman primates, AAV-DB-3 distributes widely to deep brain structures, including the striatum, and into the cortex — the outer layer of the brain where somatic CAG expansion is also known to occur, Yohrling noted.

When LTS-201 was administered to the brain of a mouse model of Huntington’s, it led to dose-dependent decreases in CAG expansion, suggesting that “we’re lowering MSH3 and … reducing CAG expansion,” he said.

In healthy nonhuman primates, the treatment also resulted in a dose-dependent decrease in MSH3 mRNA levels, and of up to 94% specifically in MSNs, which Yohrling said “provides evidence that the therapy can reach and engage its intended target in a large brain.”

The treatment mostly remained in the brain and spinal cord and was almost undetectable in peripheral tissues such as the heart and lungs, which Yohrling said is important because “our goal is to treat the brain … while minimizing unnecessary exposure to peripheral tissues.”