Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older individuals (Askanas and Engel, 2008). Accumulation of amyloid-β protein, and especially of its longer fragment Aβ42, appears to play a crucial role in s-IBM pathogenesis. In this paper Kitazawa et al. report interesting findings, using one of their transgenic mouse models overexpressing human Aβ precursor protein (AβPP). This model resembles some pathologic aspects of s-IBM, including the presence of Aβ42 and phosphorylated-tau protein.

In this transgenic mouse model, immunization with Aβ was reported to attenuate the motor impairment and also to reduce the load of Aβ and Aβ oligomers in muscle. Accordingly, the authors proposed that “there may be real opportunities to safely pursue a clinical trial in IBM patients.”

However, the reportedly improved mice are not human, and cautions are necessary in attempting to translate those results into therapeutic trials in s-IBM patients. A previous study involving Aβ immunization of...  Read more

Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older individuals (Askanas and Engel, 2008). Accumulation of amyloid-β protein, and especially of its longer fragment Aβ42, appears to play a crucial role in s-IBM pathogenesis. In this paper Kitazawa et al. report interesting findings, using one of their transgenic mouse models overexpressing human Aβ precursor protein (AβPP). This model resembles some pathologic aspects of s-IBM, including the presence of Aβ42 and phosphorylated-tau protein.

In this transgenic mouse model, immunization with Aβ was reported to attenuate the motor impairment and also to reduce the load of Aβ and Aβ oligomers in muscle. Accordingly, the authors proposed that “there may be real opportunities to safely pursue a clinical trial in IBM patients.”

However, the reportedly improved mice are not human, and cautions are necessary in attempting to translate those results into therapeutic trials in s-IBM patients. A previous study involving Aβ immunization of Alzheimer disease patients was not beneficial, and was stopped because of dangerous meningoencephalitis side effects. Several other human immunization trials in Alzheimer disease are currently in progress, but their safety and efficacy are not yet known (to my knowledge).

s-IBM is a progressive muscle disease gradually leading to severe disability from muscle weakness, but it does not appear to affect the patients’ cognitive function or lifespan. s-IBM patients can enjoy a long, productive life, intellectually and socially. Before planning a trial of Aβ immunization in s-IBM patients, the ongoing trials in Alzheimer disease must have demonstrated long-term safety. To develop a therapeutic Aβ immunologic approach to s-IBM patients would be quite a challenge. One would need to achieve an enduring therapeutic clearance of toxic Aβ oligomers located within muscle fibers without inducing widespread cytodestructive autoimmune reactions.

View all comments by Valerie Askanas

Dr. Askanas raises some excellent points. I would add that there is still substantial resistance within the field to the idea that Aβ42 drives s-IBM, with a large number of researchers holding that the disease is purely an inflammatory myopathy. This has always struck me as puzzling, given that treatments targeting the immune system have been widely ineffective. Moving forward with a clinical trial will require overcoming this resistance. This situation shares an interesting parallel with AD, in that the success (or failure) of agents targeting Aβ42 will go a long way towards determining the true role of amyloid in the disease.

View all comments by M. Paul Murphy