Targeted Lysosomal Degradation of Mutant Huntingtin by Engineered Intrabody Peptide SM3

Huntington’s disease (HD) is a devastating neurodegenerative condition caused by a mutation in the Huntingtin gene (HTT). This leads to the production of a mutant form of the huntingtin protein (mHTT) with an extended polyglutamine (polyQ) repeat, which has a propensity to misfold and accumulate in the brain. The build-up of mHTT in neurons, especially within the striatum, eventually results in severe neuronal loss and functional decline. To date, no curative treatments are available.

A novel approach to counteracting neurodegenerative diseases is the targeted reduction of misfolded proteins. Various methodologies like RNA interference and CRISPR/Cas9 have been explored, but recent clinical trial failures underscore the need for alternative strategies, especially once mutant proteins have accumulated extensively.

Researchers have turned their attention to intrabodies – engineered antibodies that operate within cells – as potential therapeutic agents. Their goal is to design intrabodies that specifically target and degrade mHTT. In a groundbreaking development, a research team from China identified a small fragment of an intrabody, termed SM3, which can bind to mHTT and direct it for degradation in the lysosomes – cellular structures responsible for breaking down unwanted materials1.

Previously, intrabodies were too large to effectively penetrate the brain. However, the SM3 peptide, at approximately 5 kDa, is substantially smaller, allowing better access to brain tissues. Critically, SM3 selectively binds mHTT without affecting the normal huntingtin protein, ensuring therapeutic specificity.

In preclinical studies on HD mice, both direct brain injections and systemic administrations of AAV-PHP.eB produced at PackGene Biotech to express SM3 resulted in significant reductions of mHTT levels. Notably, the treatment also improved motor function deficits and rectified some of the genetic dysregulation associated with the disease.

This promising strategy hinges on the lysosome’s capacity to degrade large or misfolded proteins efficiently. By combining an intrabody fragment with a lysosomal targeting signal, the researchers may have unveiled a transformative approach not just for HD, but potentially for other neurodegenerative diseases characterized by protein misfolding, like Alzheimer’s and Parkinson’s.

Delivering an intrabody fragment equipped with a lysosomal targeting signal through AAV holds great promise in addressing misfolded protein aggregates, offering a potential breakthrough in the treatment of various neurodegenerative diseases. At PackGene Biotech, we are unwavering in our dedication to advancing AAV production methods, ensuring the reliable delivery of premium AAVs, from the research phase to clinical applications. With our deep expertise and steadfast commitment, we are here to support and strengthen your endeavors in the pursuit of innovative therapies.

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