mRNA gene therapy trial in the mouse lung

Michael S D Kormann,^{1, 3} Günther Hasenpusch,¹ Manish K Aneja,¹ Gabriela Nica,¹ Andreas W Flemmer,² Susanne Herber-Jonat,² Marceline Huppmann,² Lauren E Mays,³ Marta Illenyi,¹ Andrea Schams,¹ Matthias Griese,¹ Iris Bittmann,⁴ Rupert Handgretinger,³ Dominik Hartl,³ Joseph Rosenecker¹ & Carsten Rudolph¹.  

^{1) Department of Pediatrics, Ludwig Maximilian's University Munich, Munich, Germany.}

^{2) Division of Neonatology, Children's Hospital and Perinatal Center, Grosshadern, Ludwig Maximilian's University Munich, Munich, Germany.}

^{3) Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany.}

^{4) Institute for Pathology, Diakonien Hospital Rotenburg (Wümme) LTD, Rotenburg (Wümme), Germany.}

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Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days.

Diseases caused by insufficiently expressed or defective proteins can be treated by administering functionally active protein, genetically encoded protein precursors, the corresponding gene (DNA) or that gene's transcript (mRNA). Before mRNA can be employed as a "shuttle" for therapeutic transcripts, however, its nucleotide structure must be modified to achieve the necessary stability and to prevent unwanted immune reactions. The desired characteristics can be attained with specific nucleotide modifications and the imitation of endogenous mRNA (patents DE 10 2009 035 507.3; DE 10 2009 050 308.0; PCT/EP 2010/004681). In a paper recently published in Nature Biotechnology, Kormann et al. show that a) the intramuscular administration of modified erythropoietin mRNA in mice raises hematocrit levels and b) the intratracheal application of modified surfactant protein B (SP-B) mRNA in a transgenic mouse model resulted in therapeutically sufficient SP-B expression and thus the survival of the mice. Human SP-B deficiency is a rare hereditary disease that leads to respiratory arrest and death in infants in the first year of life. There is currently no therapeutic option available for these patients aside from lung transplantation. The disease can be simulated with the aid of a transgenic SP-B knockout mouse model, in which SP-B expression is dependent on the administration of doxycycline. If the administration of doxycycline via the mice's drinking water is stopped, their lungs cease to express SP-B, and the mice develop the same typical lung symptoms as humans and die of respiratory arrest within five days. Two applications of intratracheally sprayed modified SP-B mRNA per week led to sufficient SP-B expression in the mouse lung to protect the mice from respiratory arrest and ensure healthy lung histology over the duration of the four-week treatment period. This study shows the fascinating potential of transcript therapy for the treatment of hereditary diseases of the lung for which no other therapy is available to date. With the aid of mRNA therapy, it is possible to precisely control endogenous protein expression, while at the same time minimizing immune activation and avoiding the danger of insertional mutagenesis.

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Dr. rer. nat. Michael Kormann

AG Gene Therapy

University Children's Hospital - Department I (Prof. Handgretinger)

Section for Pediatric Infectiology and Immunology (Prof. Hartl)

Wilhelmstrasse 31

72074 Tübingen, Germany

Tel. +49 7071/29-8 43 05

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