Treatment for Methylmalonic Acidemia
  • OTS
  • May 6, 2018

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Treatment for Methylmalonic Acidemia

Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia

An D, Schneller JL, Frassetto A, Liang S, Zhu X, Park JS, Theisen M, Hong SJ, Zhou J, Rajendran R, Levy B, Howell R, Besin G, Presnyak V, Sabnis S, Murphy-Benenato KE, Kumarasinghe ES, Salerno T, Mihai C, Lukacs CM, Chandler RJ, Guey LT, Venditti CP, Martini PGV.

Cell Rep. 2017 Dec 19;21(12):3548-3558

The therapeutic application of messenger RNA has largely focused on its use for vaccination due to issues with tissue specific delivery, mRNA degradation and repeat administration. However, the progress in engineered lipid nanoparticles (LNPs) in the last ~6 years, has largely overcome these difficulties.

For more background on mRNA therapeutics, please read the Perspective article on mRNA vaccination for ZIKA virus here or listen to this TEDx talk by Stephane Bancel, CEO of Moderna Therapeutics:

In this paper, An, Schneller and colleagues from Moderna Therapeutics describe the use of a pseudoU-modified codon-optimized mRNA encapsulated in biodegradable LNPs for the treatment of methylmalonic acidemia/aciduria (MMA) in two mouse models of the disease. MMA is a devastating metabolic disorder most commonly caused by a deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). Enzyme replacement therapies for mitochondrial enzymopathies are not available due to the difficulties of intracellular delivery of recombinant proteins, so there is a large unmet medical need.

Here the authors demonstrate that a single 0.5 mg/kg IV injection can decrease plasma concentrations of methylmalonic acid by up to 90 % (at 24 h) in Mut-/-;TgINS-MCK-Mut mice, a mouse model recapitulating the severe form of the disease. This effect was sustained with ~50 % downregulation evident at 10 d and 40 % at 14 d. Five weekly injections of 0.2 mg/kg followed by a 10-day washout period significantly improved survival (7 of 7 in treatment compared to 1 of 12 in untreated + control group) and growth (40% weight gain in treatment group) in these mice. Similar results were achieved in hypomorphic Mut-/-;TgINS-CBA-G715V mice, a less severe model, with single doses of up to 0.2 mg/kg. Repeat dosing (up to 5 times at 0.2 mg/kg) in these mice did not result in liver toxicity, increases in inflammatory markers in serum collected 24 h after the last injection or anti-hMUT antibody.

Why you should read this paper

This paper shows that mRNA therapy using LNP delivery to the liver can restore currently ‘‘undruggable’’ targets such as transmembrane or intracellular proteins and could thus be a viable therapeutic alternative to viral gene therapy for liver disease.