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Published on: October 3, 2011
Reducing huntingtin by immunotherapy delays disease progression in a mouse model of Huntington disease
Stefan Bartl1, Yuanyun Xie2, Nalini Potluri3
1HD Immune, Vienna, Austria.
Insights
A new antibody therapy targeting mutant huntingtin protein (mtHTT) shows promise for Huntington disease (HD). Systemic treatment in mice improved motor function and reduced disease markers, suggesting a potential new treatment strategy for this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Huntington disease (HD) is caused by mutant huntingtin (mtHTT) protein, affecting the brain and periphery.
- mtHTT is widely expressed, indicating HD is a systemic disorder.
- Current treatments focus on managing symptoms, not the underlying cause.
Purpose of the Study:
- To investigate the therapeutic potential of a novel monoclonal antibody (mAb C6-17) against extracellular mtHTT in vivo.
- To determine if systemic administration of mAb C6-17 can reduce mtHTT burden and improve outcomes in a mouse model of HD.
- To establish proof of concept for antibody-based passive immunization as an HD treatment strategy.
Main Methods:
- Development of mAb C6-17 targeting a specific region of HTT near the Caspase 6 cleavage site.
- Systemic administration of mAb C6-17 to YAC128 HD mice.
- Assessment of mAb C6-17 distribution to peripheral and central nervous system (CNS) tissues.
- Evaluation of HTT protein levels, body weight, motor behaviors, and striatal pathology (EM48 immunoreactivity).
Main Results:
- Systemic mAb C6-17 treatment successfully distributed to both peripheral and CNS tissues.
- mAb C6-17 treatment led to a reduction in HTT protein levels in YAC128 mice.
- Treated mice exhibited improved body weight, enhanced motor behaviors, and delayed progression of motor deficits.
- Reduced striatal EM48 immunoreactivity was observed in mAb C6-17 treated animals compared to controls.
Conclusions:
- Systemic administration of mAb C6-17 is a feasible therapeutic strategy for reducing mtHTT burden in vivo.
- Antibody-based passive immunization targeting extracellular mtHTT demonstrates therapeutic efficacy in a preclinical HD model.
- This approach offers a potential new treatment modality for Huntington disease.
Abstract:
In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6-17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6-17 can block cell-to-cell propagation of mtHTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether extracellular mtHTT could be therapeutically targeted in YAC128 HD mice. In a series of proof of concept experiments, we found that systemic mAB C6-17 treatment resulted in the distribution of the mAB C6-17 to peripheral and CNS tissues and led to the reduction of HTT protein levels. Compared to CTRL mAB or vehicle treated mice, the mAB C6-17 treated YAC128 animals showed improved body weight and motor behaviors, a delayed progression in motor deficits and reduced striatal EM48 immunoreactivity. These results provide the first proof of concept for the feasibility and therapeutic efficacy of an antibody-based anti-HTT passive immunization approach and suggest this modality as a potential new HD treatment strategy.
