The researchers tested new molecules in human cell cultures with varying genetic defects, consistently reducing mutant protein levels.
By Pesach Benson, TPS
Israeli scientists unveiled research showcasing the potential of two small molecules to significantly mitigate the effects of Huntington’s disease, offering hope for people afflicted with the disorder.
People with Huntington’s disease — a hereditary neurodegenerative disorder that affects the brain — experience a range of symptoms that progressively worsen over time.
Symptoms, which typically first surface around the age of 40, affect movement, cognition, and behavior, and can significantly impact an individual’s quality of life.
The disorder is caused by a genetic mutation. There is no cure for Huntington’s disease and treatment focuses on managing the symptoms through medication, therapy, and assistive devices.
A team of researchers from the Weizmann Institute in Rehovot led by Prof. Rivka Dikstein delved into the intricate mechanisms underlying Huntington’s disease.
Specifically, the disease stems from a repetitive DNA segment in a gene called huntingtin. People with the disorder have two huntingtin proteins — one normal, and the other mutated.
This triggers the production of defective proteins that stick together, forming a toxic residue that causes inflammation in the brain and thwarts the expression of genes vital for the survival of nerve cells.
The residue also causes lasting damage to mitochondria, which the researchers describe as “cellular power stations.”
Previous efforts to treat each mechanism separately were not sufficiently effective.
Moreover, drugs aimed at tackling the root of the problem – the defective huntingtin protein itself – found it difficult to distinguish between the mutated and the normal proteins.
However, a glimmer of hope emerged in 2019 when Dr. Anat Bahat of the Weizmann Institute and her colleagues identified certain small molecules capable of inhibiting the expression of mutant huntingtin without impeding the production of normal proteins or exacerbating inflammation.
Building upon this finding, worked to identify the most potent inhibitors among a pool of structurally similar molecules.
After meticulous screening processes involving cell cultures from both mouse models and human patients, the researchers identified two standout molecules.
The researchers then tested the new molecules in cell cultures from human patients with varying degrees of genetic defect, and in every case, identified a significant drop in the amount of the mutant protein.
At the same time, there was no decrease in the expression of the nonmutant protein – evidence that the new molecules were doing their job with great precision.
Whether injected or administered orally, the molecules maintained their effectiveness at crossing the blood-brain barrier, a protective wall of cells surrounding the brain.
Notably, one of the molecules exhibited pronounced therapeutic effects at lower doses, albeit with an impact on a wide array of genes.
The second molecule, which required higher doses, induced fewer adverse side effects.
Mice subjected to the treatment showed mitigated symptoms, including reduced anxiety levels and preserved motor function.
The Weizmann team’s findings were recently published in the peer-reviewed EMBO Molecular Medicine.