Novel approach for treating mitochondrial disorders wins Kaye prize

A novel concept for the treatment of mitochondrial disorders using directed enzyme replacement therapy (DERT) has won for a Hebrew University of Jerusalem doctoral candidate one of this year's Kaye Innovation Awards. The awards were presented at this year's 71st meeting of the Hebrew University Board of Governors.

DERT is a therapeutic approach to metabolic disorders whereby the deficient or absent enzyme is artificially manufactured with the addition of a delivery component and is administered to patients on a regular basis.

Mitochondria are special little organelles within the cells (organelles are small, unique structures within the cells that perform specialized tasks). The mitochondria play a critical role - most of the numerous biochemical pathways and reactions are performed within them. However, their most important job is to generate energy out of food and to discard toxic metabolites. (Metabolites are substances produced by a metabolic reaction.)

Inside the mitochondria there are thousands of enzymes that carry out all these reactions. If one of these enzymes is damaged or deficient due to a genetic mutation, a mitochondrial metabolic disorder occurs. Modern medicine offers no cure for mitochondrial disorders (among which are mitochondrial myopathies, maple syrup urine disease and many others). The standard treatment is only palliative, with the aim of improving, postponing or circumventing the massive damage caused by the over- production of free radicals, the accumulation of toxic metabolites and the low rate of energy production.

Matan Rapoport, a Ph.D. student in the Department of Cellular Biochemistry and Human Genetics at the Hebrew University Faculty of Medicine, demonstrated the effectiveness of DERT by treating the mitochondrial disorder lipoamide dehydrogenase (LAD) deficiency. LAD deficiency is an inherited recessive disorder, which results in extensive metabolic disturbances due to a reduction in the activity of the LAD enzyme within the mitochondria.

The clinical course of LAD deficiency is variable, presenting in infancy as a neurological disease of varying severity, or later in life with life-threatening recurrent episodes of liver failure. Most LAD deficiency patients suffer from neurological symptoms.

In developing DERT, Rapoport proposed a novel but simple approach for the delivery of an artificial mitochondrial enzyme directly to its sub-cellular location. The approach is to fuse the manufactured LAD enzyme with a specific delivery component, which will then lead the LAD into the cells and their mitochondria. There, it will substitute for the mutated endogenous enzyme.

For the past four years, Rapoport, under the guidance of Hebrew University Prof. Haya Loberboum-Galski, has been experimenting in vitro on cells taken from patients suffering from LAD deficiency. The results have been highly positive. Experiments are also now being conducted on the in-vivo model of this disorder in LAD-deficient mice. Very promising preliminary results show the ability of this therapy to improve LAD enzymatic activity even in the mouse brain.

Rapoport's invention of enzyme replacement therapy for mitochondrial disorders is patented by Yissum, the Technology Transfer Company of the Hebrew University of Jerusalem. This invention possesses great potential to becoming the treatment of choice for various types of mitochondrial disorders and consequently encompasses a significant commercial potential, as today there is no known medical cure.

The Kaye Innovation Awards, one of which went to Rapoport, have been given annually since 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff and students of the Hebrew University to develop innovative methods and inventions with good commercial potential which will benefit the university and society.

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