Transthyretin amyloidosis (ATTR) is a rare, progressive, and ultimately fatal condition characterized by theabnormal extracellular deposition of transthyretin (TTR) protein within the peripheral nerves (ATTR-PN) and/orwithin the heart (ATTR-CM). There are two types of ATTR: (1) hereditary ATTR (hATTR), where the destabilizingmutation in the TTR-gene is inherited, or (2) ATTRwt, in which people with the wild-type TTR-gene sequencedevelop the disease sporadically. Recent estimates put the worldwide number of people affected by ATTR atapproximately 500,000; however, these patient populations are thought to be significantly underdiagnosed.In recent years, the first therapeutics have been approved to treat ATTR either through stabilization of TTR witha small molecule (tafamidis and diflunisal) or reduction of TTR expression levels through antisenseoligonucleotides (patisiran and inotersen). However, not all patients respond to treatment and those that dorespond continue to decline; disease progression is slowed but not reversed.The path from normal TTR to amyloid deposition proceeds through a monomeric intermediate and it ishypothesized that the reason patients continue to decline is due to its continued presence. Targeting the entityimplicated in aggregation, the dissociated monomeric intermediate, could lead to a better therapeutic approachwhere the total pool of native TTR remains unaltered and only the aggregation prone intermediate is removed.Hence, the ADRx approach is to use a proprietary antibody to bind this intermediate aggregating species andclear it from the patient's blood. An antibody is an ideal approach for this therapeutic due to its long half-life, highaffinity, exquisite specificity, and availability of the intermediate within the bloodstream.Through a proprietary antibody discovery program, highly potent and specific monomer binding antibodies havebeen discovered. One of these antibodies will be used to perform proof-of-concept experiments in mice toevaluate its ability to deplete these aberrant aggregation-prone monomers from the blood of mice.Novel ATTR therapeutic development efforts have been hindered by the lack of readily available animal modelsto test efficacy. While transgenic animal models have been developed to mimic TTR deposition in mice, thesemodels poorly replicate the TTR deposition patterns found in human ATTR patients and furthermore show greatvariance in amount, type, and location of deposition. Additionally, these models can take months for depositionto occur, in some cases upwards of 24 months. In the following application we propose studies to show that ourproprietary antibody can efficiently find and clear the TTR intermediate within an animal on a short timescale.If successful, these experiments will show the depletion of the aggregating form of TTR from an animal for thefirst time. This will establish the first step in preclinical development of these antibodies towards a therapeuticthat can be used in ATTR patients as a stand-alone therapy or in combination with other approved drugs.
Public Health Relevance Statement: NARRATIVE
Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by the accumulation of aggregated
transthyretin (TTR) protein within tissues, such as the heart and nervous system. Although therapeutic
treatments are available, they do not reverse ATTR and hence patients continue to decline. ADRx proposes
studies to validate that a proprietary antibody may function as a therapeutic that unlike current treatments,
presents great potential to arrest the ATTR disease.
Project Terms:
