mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice

Abstract

Thrombotic thrombocytopenic purpura (TTP) is primarily caused by deficiency of ADAMTS13 within the blood stream due to either genetic defects or presence of inhibitory autoantibodies. Preclinical and clinical studies suggest that enzyme replacement therapy with recombinant human ADAMTS13 protein (rhADAMTS13) is effective and safe in treatment of TTP. However, frequent dosing would be required due to the relatively short half-life of rhADAMTS13 in circulation as well as the presence of inhibitory autoantibodies that collectively result in the poor pharmacological profile of rhADAMTS13. With technical breakthroughs in exploring mRNA as therapeutics, we hypothesized that restoration of ADAMTS13 activity for a prolonged duration of time can be achieved through systemic dosing of mRNA, wherein the dosed mRNA would utilize hepatic cells as bioreactors for continuous production of ADAMTS13. To test this hypothesis, mRNA encoding human ADAMTS13 WT or an ADAMTS13 variant, that had demonstrated resistance to predominant clinical TTP autoantibodies, was formulated in lipid nano-particles for liver-targeted delivery. In both ADAMTS13-sufficient and -deficient mice, a single dose of the formulated mRNAs at 1 mg/kg resulted in expression of hADAMTS13 at or above therapeutically relevant levels in mice for up to five days. This proof-of-concept study suggests that mRNA therapy could provide a novel approach for TTP treatment.

mRNA as novel technology for passive immunotherapy

“…Thereafter, it took almost two decades until further studies started to demonstrate the broad potential of mRNA-based protein therapies. Meanwhile, there is a plethora of publications on a huge variety of indications comprising anemia [188,218], hemophilia [223,224], myocardial infarction [155,225], cancer [226,227], lung disease such as surfactant B deficiency and asthma [228][229][230], metabolic disorders [231][232][233][234][235], fibrosis [195], skeletal degeneration [236], tendon impairment [237], and neurological disorders such as sensory nerve dysfunction, Friedreich's ataxia and Alzheimer's disease [238][239][240]. Whereas evidence for the therapeutic potential of mRNA is mostly restricted to mouse models, first data in swine indicate that mRNA-based protein therapies are feasible also in large animals [218,225].…”

Optimization of 5′ Untranslated Region of Modified mRNA for Use in Cardiac or Hepatic Ischemic Injury

“…In parallel, other groups are using the modRNA platform in preclinical studies of different liver diseases to deliver different target genes. The different liver disease models that have been used are for factor IX deficiency hemophilia B, 42 acute intermittent porphyria, 43 glycogen storage disease type 1A, 44 thrombotic thrombocytopenic purpura, 45 alpha-1 antitrypsin deficiency, 46 Crigler-Najjar syndrome type 1, 47 and urea cycle disorder 48 with target genes of FIX, PBGD, glucose-6-phosphatase, ADAMTS13, SERPINA1, bilirubin-UGT, and ornithine transcarbamoylase, respectively. As was described above, both the heart and liver disease have been heavily studied in search for new treatments.…”

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

“…delivery has been used in studies addressing protein replacement. [51][52][53][54] In this review, we focus on non-viral delivery systems for in vivo delivery of mRNA to the liver. Such delivery systems can be broadly categorized into two groups, namely, lipids or lipid-like materials and polymers.…”

“…Many novel gene therapeutic options have Review been investigated in preclinical studies. [99][100][101] In the recent work by Liu-Chen et al, 53 a full-length optimized ADAMTS13 mRNA was synthesized and encapsulated into LNPs. Upon a single i.v.…”

“…This therapeutic approach could provide a treatment for patients with a steady supply of secreted enzyme for a few days while still waiting for liver transplantation. 53 Glycogen Storage Disease Type 1A…”