**4. Amyloidosis and the nervous system**

Neurologic involvement of systemic amyloidosis has been observed in over 20% of cases, and the median duration of neuropathic symptoms prior to diagnosis is 2 years [43]. The pathophysiology of amyloid deposition contributing to the clinical manifestation of neurodegenerative disorders, including Alzheimer's Dementia, Parkinson's Disease, and Huntington's Disease, has been well-documented [44]. Furthermore, cerebral amyloid angiopathy is a well-known cause/risk factor for intracerebral hemorrhage in the elderly [45]. Lastly, systemic amyloidosis (classically, primary amyloidosis) affects not only the central nervous system, but is a well-known cause of peripheral and autonomic neuropathy [46]. Thus, the deposition of abnormally folded proteins has not only been linked to progressive and acute devastating CNS disorders, but also to neurologic sequelae throughout the body. In this section, we describe some of the novel treatments and their mechanisms of action for both CNS and PNS manifestations of the illness.

## **4.1 Amyloid beta: Alzheimer's dementia, and cerebral amyloid angiopathy**

There are no current therapies that modify the deposition of A beta amyloid in the CNS. Therefore the focus of treatment has been mainly symptomatic with acetylcholinesterase inhibitors, antidepressants and antipsychotics. However, new research focusing on monoclonal antibodies reducing plaque load prove to have promising results in the mice model [47]. Modest levels of peripherally administration antibodies against the amyloid beta-peptide crossed the blood brain barrier entering the CNS and inducing clearance of preexisting amyloid via activation of microglial cells [48]. Bapineuzumab, Solanezumab, Gantenerumab, Crenezumab, Ponezumab, BAN2401, and Aducaumab are anti-amyloid beta monoclonal antibodies that have progressed to human trials and paved the pathway for the development of more effective therapies.

The mechanism of Bapineuzumab, one of the first humanized monoclonal IgG1 antibody used in humans, attaches to soluble and fibrillar amyloid beta via the five N-terminal residues inducing Fc receptor-mediated microglial phagocytosis of amyloid beta deposits. In phase 1, 30 patients were divided into low dose (0.5 mg/kg), medium (1.5 mg/kg) and high dose (5 mg/kg), and overall the drug was considered to be safe. 3/10 participants in the high dose category developed MRI findings typical of vasogenic edema that eventually resolved. Amyloid-related imaging abnormalities (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 eventually led to the drug's discontinuation for dementia.

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 autosomal dominant Alzheimer's disease.

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].

#### **4.2 Transthyretin amyloidosis**

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 cardiomyopathy and familial amyloidotic polyneuropathy [49, 50].

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 transthyretin production.

**29**

8–20% of patients [49, 55, 56].

*Amyloidosis: Systems-Based Therapies*

**5. Liver transplantation**

*DOI: http://dx.doi.org/10.5772/intechopen.85201*

**5.1 IDOX, doxycycline, and RNAi therapy**

binding sites between IDOX and amyloid fibrils [52].

clearance of existing amyloid simultaneously [53, 54].

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.

Since the difficulties associated with liver transplantation prevented adequate treatment of FAP patients, new non-surgical treatment methods were researched. It was initially shown that 4′iodo′4′-doxy-doxorubicin (IDOX) inhibits amyloid formation and promotes the resorption of amyloid deposits. Initially shown that IDOX can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis, it was further studied for all types of amyloid deposition disorders. It is hypothesized that IDOX exerts its effects by inhibiting fibril growth and increasing the solubility of amyloid deposits. This, in turn, facilitates amyloid clearance. These results have been consistent in both in vivo and in vitro studies through two distinct

At around the same time as IDOX was being investigated, Doxycycline became the next promising medication that showed similar success in both FAP transgenic mice and phase II human trials with transthyretin amyloidosis. It's theorized mechanism of action involves amyloid fibril destructuration and promotion of amyloid deposition. In one phase II trial, doxycyclin plus tauroursodeoxycholic acid resulted in stable cardiac and neuropathy symptoms after 1 year of treatment. When used in conjunction with TTR stabilizers, therapy could both block formation and promote

The most recent research for transthyretin amyloidosis treatment has surrounded RNA interference (RNAi) therapy. RNAi therapy decreases transthyretin production from the liver by directly suppressing mRNA transcription of the gene that codes for the transthyretin protein. Due to the specific nature of this pharmacology, long-term side-effects of RNAi therapy have not been reported. Two medications, Patisiran and Inotersen, have become FDA approved in the past 5 years after studies have shown a dose-dependent reduction of both mutant and nonmuntant tranthyretin production and deposition. This RNAi therapy has been shown to cause between 50 and 80% reduction in transthyretin levels as early as 2–3 weeks after therapy initiation. Furthermore, these medications have provided significant neurologic symptomatic benefit in a majority of patients when compared to placebo therapy. Since these medications affect both mutant and nonmutant transthyretin production, they have been shown to not only have decreased side-effects to liver transplantation, but better long-term efficacy. The most common side effect to the medication reported has been transfusion-related reactions in
