Catabodies to Degrade Transthyretin Amyloid

A comparatively small number of misfolded proteins form solid aggregates in tissue due to the change in chemical properties caused by this misfolding, and the result is called an amyloid, and a consequent medical condition is called an amyloidosis. The best known type of amyloid is that associated with Alzheimer's disease, but for many of the others it isn't as clear as how these aggregates cause damage. Nonetheless amyloids all accumulate with age, and thus should be removed by any comprehensive suite of rejuvenation treatments.

One of the other amyloids clearly linked to harm is misfolded transthyretin (TTR), which is implicated as the cause of death in most people who make it to very advanced ages. In the very elderly this form of amyloid clogs the cardiovascular system. There is also an inherited variant of TTR amyloidosis that occurs rarely in younger people due to an unfortunate genetic mutation, and as is often the case in these matters most past research has focused there.

Here is a pointer to a recent paper that results from SENS Research Foundation funded work on one possible way to safely break down transthyretin amyloid, removing its contribution to age-related mortality through the use of catalytic antibodies, thought to be a type of functional component in the innate immune system. If selective antibodies effective at breaking down this form of amyloid are established by searching through the many different types present in humans, then these few proteins can be manufactured in bulk and used as the basis for a treatment:

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the [correctly folded] TTR (phyTTR).

IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins.

The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. Catalytic IgMs may clear misfolded TTR and delay amyloidosis [and] the innate antibody repertoire is a source of selective catabodies to toxic proteins.



The good thing about this is that the treatment looks like a standard drug. So the standard drug development pathway is open for it.

I think they now just need some good demonstrations in an in vivo model. And I think there are some mouse models of TTR amyloidosis out there as other groups are working on cures for the genetic form of this condition.

The only downside is that this only seems to be a problem in really old people, so won't lead to results that capture the publics attention.

I think the most exciting thing about this potential technology is that it may be usable against the amyloids that cause Alzheimers in the brain without causing inflammation and damage due to phagocytosis like IgG antibodies do.

Still it is untested in animal models, so there are loads of potential pitfalls yet.

Posted by: Jim at June 17th, 2014 11:17 AM

Jim has stumbled across a common misconception. All treatments developed in the SENS theme (whether or not developed by SENS RF) are going to look like standard drugs or surgeries (comparitively speaking). They are going to have the same delivery as medicine of the time because that's all any SENS therapy is, medicine.

I think when people hear the idea of transhumanism or life extension or anything else that gets lumped in with SENS is they think it's going to be a laser beam or some cyborg enhancement.

I believe it'll be things that are done, not all at the same time, as Aubrey de Grey suggests that have recovery times similar to traumatic injury like breaking a bone or recovering from an infection.

As for Transthyretin there a few Almyoidosis based dieseases which it could be applied to. In general remember that all of the SENS style therapies can be applied to one disease or another.

Posted by: Michael at June 17th, 2014 11:37 PM
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