Novel approach for treating mitochondrial disorders wins Kaye prize

Tag : fuse component

A novel concept for the treatment of mitochondrial disorders usingdirected enzyme replacement therapy (DERT) has won for a Hebrew University of Jerusalem doctoral candidate one of this year's Kaye Innovation Awards. Theawards were presented at this year's 71st meeting of the HebrewUniversity Board of Governors.
DERT is a therapeutic approach to metabolic disorders whereby thedeficient or absent enzyme is artificially manufactured with theaddition of a delivery component and is administered to patients ona regular basis.

Mitochondria are special little organelles within the cells(organelles are small, unique structures within the cells thatperform specialized tasks). The mitochondria play a critical role -most of the numerous biochemical pathways and reactions areperformed within them. However, their most important job is togenerate 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 carryout all these reactions. If one of these enzymes is damaged ordeficient due to a genetic mutation, a mitochondrial metabolicdisorder occurs. Modern medicine offers no cure for mitochondrialdisorders (among which are mitochondrial myopathies, maple syrupurine disease and many others). The standard treatment is onlypalliative, with the aim of improving, postponing or circumventingthe massive damage caused by the over- production of free radicals,the accumulation of toxic metabolites and the low rate of energyproduction.

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

The clinical course of LAD deficiency is variable, presenting ininfancy as a neurological disease of varying severity, or later inlife 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 approachfor the delivery of an artificial mitochondrial enzyme directly toits sub-cellular location. The approach is to fuse the manufacturedLAD enzyme with a specific delivery component, which will then leadthe LAD into the cells and their mitochondria. There, it willsubstitute for the mutated endogenous enzyme.

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

Rapoport's invention of enzyme replacement therapy formitochondrial disorders is patented by Yissum, the TechnologyTransfer Company of the Hebrew University of Jerusalem. Thisinvention possesses great potential to becoming the treatment ofchoice for various types of mitochondrial disorders andconsequently encompasses a significant commercial potential, astoday there is no known medical cure.

The Kaye Innovation Awards, one of which went to Rapoport, havebeen given annually since 1994. Isaac Kaye of England, a prominentindustrialist in the pharmaceutical industry, established theawards to encourage faculty, staff and students of the HebrewUniversity to develop innovative methods and inventions with goodcommercial potential which will benefit the university and society.
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