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Notice with respect to a license agreement with uniQure and the development of gene therapy encoding a new enzyme, “modified NAGA”, for Fabry disease

We, Tokyo Metropolitan Institute of Medical Science (TMIMS) executed with uniQure N.V. (Nasdaq: QURE) (*1) a license agreement in May 2018 in order to develop a gene therapy for Fabry disease (*2) using an AAV vector (*3) encoding modified α-N-acetylgalactosaminidase (modified NAGA) (*4). Modified NAGA is developed by TMIMS, Meiji Pharmaceutical University (MPU) and Altif Laboratories Inc. (ALTIF) collaboratively. We are pleased to announce that uniQure initiated preclinical development of the medicine for gene therapy for Fabry disease based on the results of their basic research.

Fabry disease is an inherited metabolic disorder that results from the accumulation of glycolipids such as globotriaosylceramide (Gb3) in the body due to lack or dysfunction of α-galactosidase (GLA). Enzyme replacement therapy (ERT) (*5) with recombinant human GLAs is available as one of the therapies for Fabry disease and it is known to have certain therapeutic effects. However, it has been reported that ERT sometimes causes adverse reactions and attenuated therapeutic effects due to antibody production against the recombinant enzymes. Modified NAGA was developed by Drs. Hitoshi Sakuraba, Yoichi Tajima and Ikuo Kawashima in TMIMS in order to resolve these problems for the GLA recombinants. Modified NAGA, which is developed by the modification of NAGA to obtain GLA activity, can degrade glycolipids such as Gb3. Compared to GLA, modified NAGA may cause less immune reactions because its molecular structure is almost the same as that of wild-type NAGA, which is present from birth in the patients who are lacking of GLA.

One of the benefits of a gene therapy is that periodical administration of an enzyme, as done in ERT may not be necessary. However, the expression of target gene cannot be easily stopped once the gene therapy starts. Therefore, compared to an enzyme medicine used in ERT, an enzyme (a gene) used for gene therapy must be highly safe. uniQure appreciated the potential safety profile of modified NAGA and has decided to study the application of gene therapy for Fabry disease with it.

TMIMS and MPU are willing to support uniQure for the development of modified NAGA to cure patients with Fabry disease and improve their QOL.

Terminology

*1 uniQure:

uniQure is a gene therapy company located in Amsterdam, Netherlands, and the first company that has obtained market authorization for a gene therapy drug in Europe. They have been developing AAV-based gene therapies and built up manufacturing facilities, and are positioned to be world leaders in the gene therapy field. Currently, they are developing gene therapy drugs for Hemophilia B and Huntington disease.

*2 Fabry disease:

Fabry disease is an X-linked inherited disease involving deficiency or reduced activity of an enzyme called α-galactosidase (GLA) in lysosomes, which results in the accumulation of glycolipids such as globotriaosylceramide (Gb3) in the body. This disease is specified as an incurable disease by the Japanese Ministry of Health, Labor and Welfare. The actual incidence rate in Japan is still unknown; however, it is estimated to be 1/8,000-9,000 according to newborn screening results so far obtained. The major signs and symptoms of this disease are pain in the hands and feet, hypohidrosis, angiokeratomas, corneal opacity, gastrointestinal symptoms, deafness, kidney problems, heart problems, cerebrovascular disorder and so on.

*3 AAV vector:

Adeno-associated virus (AAV) is capable of infecting both dividing cells and non-dividing cells, and delivering a target gene to wide range of cell types. The introduced gene can remain and be expressed for long term in most tissues. Based on these properties, currently AAV is often selected to be used as a gene therapy vector.

*4 modified α-N-acetylgalactosaminidase (modified NAGA):

Modified NAGA with changed 2 amino acids in its active site of α-N-acetylgalactosaminidase (NAGA) that give it GLA activity. The molecular structure is almost the same as that of NAGA (original NAGA), so it may not cause immune reactions to the patients who lack GLA. TMIMS and ALTIF have the substance patents including its gene.

*5 Enzyme replacement therapy (ERT):

One of the therapeutic methods for genetic disease patients who have a lack or dysfunction of a specific enzyme. The functional recombinant enzyme is administrated to the patients to improve the symptoms, however, the recombinant enzyme sometimes becomes immunogenic to patients who lacks the enzyme from the birth. Currently, therapeutic recombinant enzymes are approved for Gaucher's disease, Fabry disease, Pompe disease, Mucopolysaccharidosis typeI, II, IVa, VI, and lysosomal acid lipase deficiency.

Related paper

Use of a Modified α-N-Acetylgalactosaminidase in the Development of Enzyme Replacement Therapy for Fabry Disease,
Youichi Tajima, Ikuo Kawashima, Hitoshi Sakuraba, et al., Am J Hum Genet, 85(5):569-580, 2009

Patents

1. “Novel highly functional enzyme having modified substrate-specificity” (PCT/JP2006/323509), Applicants: TMIMS and ALTIF
2. “Pharmaceutical composition for enzyme replacement therapy” (PCT/JP2008/59604), Applicants: TMIMS and ALTIF

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