**6. Therapeutic approaches to amyloid pathophysiology**

As described above, once formed, amyloid fibrils are intrinsically quite stable due to intra- and intermolecular bonds and relative inaccessibility to proteases. Ideally, disrupting the fibrils themselves would be an appropriate approach to treating at least some amyloid disorders. In this regard, chaotropic molecules (e.g., urea, guanidinium, etc.), often used in the laboratory, are not options for treatment due to their toxicity. Alternative agents, compatible with in vivo use have not yet been identified. Thus, successful intervention(s) for amyloid disorders must either prevent formation of the precursor(s) or stabilize the protein predecessors of oligomers (or their proteolytic cleavage). Several approaches have been introduced, and these depend upon the *specific* type of amyloidosis (recall **Table 1**).

Immunoglobulin light chain overproduction ("primary" amyloidosis) is basically a clonal disorder of plasma cell proliferation/overexpression. Here, treatment generally depends on suppression or elimination of the responsible cell population. This falls into the spectrum of treatment of myeloma and related disorders and depends on oncologic approaches.

Amyloid A (SAA) disorders ("secondary" amyloidosis) generally reflect overproduction of the SAA precursor. These usually are related to chronic or periodic and recurrent infection/inflammation. The incidence of these has been reduced by successful treatment of conditions such as tuberculosis and osteomyelitis. However, these and other types of infections and inflammation remain prominent in certain parts of the world and can be accompanied by amyloidosis. Genetic disorders such as familial Mediterranean fever with recurrent, self-limited inflammatory episodes can usually be controlled with agents such as colchicine [23], minimizing SAA synthesis and AA amyloid accumulation.

For TTR-related disorders several approaches are recognized. First, because the liver is the main site for the synthesis of TTR, liver transplantation can eliminate production of the mutant TTR protein. Although this has been used successfully, it is a complex process with its own intrinsic short- and long-term complications [24]. Second, synthesis of the responsible mutant protein can be suppressed. Several approaches based on specifically interrupting stability of TTR messenger RNA through RNAi have been developed. (Carriers of TTR mutations are usually heterozygotes, so these approaches generally reduce levels of both mutant and normal TTR—apparently, a reduced concentration of TTR is well-tolerated.) Third, the circulating tetramer can be stabilized by exogenous agents (e.g., Tafamidis™) to shift the equilibrium away from dissociation (and, hence, minimize oligomer formation). These approaches show promise [25, 26].

For neurologic disorders where the underlying problem is likely intracellular (e.g., α-synuclein and β-protein), the above approaches have not been feasible. It is more likely that clarification of complex intracellular pathways will be required in order to develop approaches to prevent and/or interrupt fibril accumulation in these and related conditions.
