Genetic therapy for Krabbe disease extends life of mice

Mendelian disorders – although genetically simple – can pose significant challenges in the development of gene therapy. In the case of Krabbe disease, even animal models were hardly ever cured. However, new optimized treatment has achieved a 3-fold increase in life length.

Krabbe disease is caused by a mutation in the gene GALC. Its carriers have disrupted metabolism in nervous system cells. First symptoms are usually present before reaching the 6th month of life. Most of Krabbe disease patients have a very short life span, not exceeding 2 years on average.

Genetic modification is an obvious method of choice for Krabbe disease. The actual correction of mutations is not even required, as a patient should benefit from the simple addition of a new healthy copy of the gene. Despite that, preclinical trials in animal models (twitcher mice) were unexpectedly disappointing. Previous best results managed to extend life by 75%.

A new approach from Universities of Missouri and Kansas tripled that result to 275% on average. Scientists have changed the therapeutic viral carrier – adeno-associated virus. They used AVV serotype 9 and optimized it for entering the brain, as well as for better production of a protein from the gene.

Mice received single intravenous injection only, early after birth. The animals lived up to 180 days, in contrast to untreated cases where the life span was 40 days on average. Later injection (6 – 12 days after birth) also helped to extend life, although shorter – up to 112 days.

A combination of newly developed therapy with other approaches (such as bone marrow transplantation and multiple injections) can bring a significant extension of life. Implications, inter alia, are discussed here.

Publication: Pan, X., Sands, S. A., Yue, Y., Zhang, K., LeVine, S. M., & Duan, D. (2019). An engineered galactosylceramidase construct improves AAV gene therapy for Krabbe disease in twitcher mice. Human gene therapy. Doi:10.1089/hum.2019.008.

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