**5. Liver transplantation**

*Amyloid Diseases*

(ARIA) were coined to describe imaging abnormalities as a result of treatment, for example ARIA-H for microhemorrhage and hemosiderosis and ARIA-E for effusion or vasogenic edema. IV infusion in phase 2 of the trial showed no significant treatment differences in patients with mild to moderate Alzheimer's disease. A parallel phase 2, as well as retrospective study done by neuroradiologists resulted in the conclusion that there is an increased occurrence of ARIA-E in carriers of APOE4, necessitating the incorporation of biomarkers to qualify for treatment, but increased numbers of symptomatic ARIA-E resulted in discontinuation of bapineuzumab trials. Solanezumab, another humanized IgG1 monoclonal antibody, completed phase 3 testing without meeting efficacy requirements. It binds the mid-domain of amyloid beta residues to increase clearance of monomers, and continues in preclinical Alzheimer's disease trials to see if there is a benefit to earlier intervention. Phases 1 and 2 showed a relationship between dose and CSF Amyloid-beta protein. In phase 3 studies, termed EXPEDITION 1 and EXPEDITION 2, 18 month trials of IV solanezumab 400 mg against IV placebo, did not demonstrate any significant benefit. However, it demonstrated the drugs favorable safety profile with only 0.9% incidence of ARIA-E compared to 0.4% seen in the placebo. A third phase 3 trial, EXPEDITION 3, also showed nonsignificant results with solanezumab and eventu-

As opposed to the previously mentioned therapies, Gantenerumab was the first fully human IgG1 antibody against the conformational epitope expressed on amyloid beta fibrils that contain both the N-terminal and central amino acids. Phase 1 trials with patients who had mild to moderate Alzheimer's disease showed that seven IV infusions (60–200 mg) every 4 weeks reduced brain burden. It also showed the drug's favorable safety profile. 2 out of 6 patients in the high dose group experienced ARIA-E. Initial phase 2 trials included 360 participants and doses of subcutaneous 105 mg or 225 mg every 4 weeks for 2 years, but was later expanded to a phase 2/3 with 799 participants showed no significant treatment effects for CDE-SB or changes in the amount of brain amyloid beta. Currently Gantenerumab, like solanezumab, is being explored for patients with fast progression and autoso-

Other therapies that have proven to have non-significant results in the treatment of amyloid beta deposition within the CNS include Crenezumab, Ponezumab, BAN2401, and Aducaumab. Despite these findings, the tolerability of monoclonal antibodies lends hope for developing therapies for this pathology. Moreover, future studies should focus on the importance of brain entry of anti-amyloid beta monoclonal antibodies, as it is not currently clear whether therein lies any benefit as only 0.1% cross the blood brain barrier. Dosage and stage of disease are two other important points for consideration in improving the efficacy of these therapies, and whether the lack of efficacy was due to insufficient amounts of drug or late stage disease [49].

Transthyretin is a liver-derived protein, that when misfolded can accumulate in the liver, kidney, GI tract, and the peripheral nerves. Multiple genetic abnormalities have been shown to contribute to increased predisposition and familial forms of transthyretin amyloidosis. These have led to syndromes such as familial amyloidotic

Familial amyloidotic polyneuropathy (FAP) is a fatal condition that is caused by the substitution of a methionine residue for a valine residue at the 30th position of the TTR gene [51]. In this section, we briefly discuss the role of liver transplantation and more thoroughly introduce the use of RNA interference molecules to decrease

cardiomyopathy and familial amyloidotic polyneuropathy [49, 50].

ally led to the drug's discontinuation for dementia.

mal dominant Alzheimer's disease.

**4.2 Transthyretin amyloidosis**

transthyretin production.

**28**

Around 95% of transthyretin is produced by the liver, and thus, it was postulated that liver transplantation would provide great benefit for patients with transthyretin amyloidosis. The first liver transplantation for transthyretin amyloidosis was done in 1990 in Sweden and showed promising results. Since then, liver transplantation has been a standard treatment for this devastating disorder [51].

Liver transplantation has been shown to be of benefit if intervention is taken earlier in the disease course. The risks and prognostic factors for liver transplantation have been well-documented, including the long wait times for an available transplantable organ. However, additional prognostic factors for survival post liver transplantation in patients with amyloidotic polyneuropathy include hereditary and geographic factors, duration of the disease, initial degree of polyneuropathy, presence of autonomic dysfunction, co-morbid cardiac, kidney/bladder, and GI impairment, and prior nutritional status. Liver transplantation is usually not a procedure that will improve the patient's condition, but rather, prevent further decline.
