ASPR

10:00-11:30, Saturday, April 17, 2010
Symposium 8–New Treatments for Genetic Diseases in Children
Moderators: Wuh-Liang HWU (Taiwan), Yoshikatsu ETO (Japan)
MS8-01	Novel biological Therapies for Inherited Disease in Children: Lessons from Animal Models and Clinical Studies	Barry J. BYRNE (USA)
MS8-02	Novel Treatments and Lessons in Lysosomal Storage Diseases	Yoshikatsu ETO (Japan)
MS8-03	Emerging Therapies for Neuropathic Lysonsomal Storage Disorders	Seng H. CHENG (USA)

MS8-02

Novel Treatments and Lessons in Lysosomal Storage Diseases

Yoshikatsu ETO (Japan)

Novel Treatments and Lessons in Lysosomal Storage Diseases
Yoshikatsu Eto
Department of Genetics & Genome Science, Tokyo Jikei University，School of Medicine, Tokyo, Japan

Lysosomal Storage diseases(LSD) are caused by a single lysosomal enzyme deficiency which results in the accumulation of a certain compounds such as glycolipids, mucopolysaccharides or glycopeptides in lysosomes. More than 60 different LSDs have been described in the literatures. Treatment options have been increased greatly recently; these are enzyme replacement therapy(ERT), hematopoietic stem cell therapy, (HSCT) chemical chaperon therapy, substrate reduction therapy gene therapy and etc.

Enzyme replacement therapy are now widely used in many LSD patients such as Gaucher, Fabry, Pompe, MPS I, II, VI diseases. However, there are drawbacks with ERT. :these are high costs, IgG antibody formation toward CRIM negative patients and no efficacy to CNS involvement. On the other hand, HSCT does cross the blood brain barrier, but poses problems, such as GVHD, rejection and etc. Chaperon therapy has some benefit( oral administration), but limited efficacy to the type of mutation.

Substrate reduction therapy such as Zavesca and Genz has been explored to Gaucher, Fabry and Pompe diseases. The results seem to be also limited in their efficacies.

Novel treatments such as exon skipping procedure (PTC) and SiRNA may be also explored in future. Gene therapy using AAV vector has been carried out in patients with Ceroid lipofucinosis and possibly in metachromatic leukodystrophy.by lenti virus vector. Now, number of treatment choices for the patients with LSD are available, but there are still currently being evaluated situation.

MS8-03

Emerging Therapies for Neuropathic Lysonsomal Storage Disorders

Seng H. CHENG (USA)

Emerging Therapies for Neuropathic Lysonsomal Storage Disorders
Seng H. Cheng
Group Vice President, Genetic Diseases Science, Genzyme Corporation

While systemic administration of recombinant enzymes can be effective at treating the visceral disease associated with several lysosomal storage disorders, this approach does not adequately address the CNS component because of the limited ability of the hydrolases to traverse the blood brain barrier. To overcome this limitation, we have investigated alternate delivery strategies such as direct administration of the enzymes into the CNS, and evaluated other technology platforms including gene and small molecule therapies. Our experience with intracerebroventricular administration of recombinant acid sphingomyelinase (ASM) into the CNS of Niemann-Pick A mice showed that this route of delivery could result in broad dispersion of the therapeutic throughout the CNS. Near-global correction of the storage pathology was realized in the CNS of the treated mice with consequent improvement in motor function. Amounts of the enzyme were also detected in the serum with resultant partial correction of the visceral disease suggesting that direct and periodic delivery of enzyme into the brain may be an approach to treating this disease. We have extended these observations to mouse models of late-infantile Battens disease and neuropathic Gaucher disease suggesting that this therapeutic paradigm may be broadly applicable to other lysosomal storage disorders. Intracerebroventricular delivery of the respective lysosomal enzymes into these mice reduced the levels of the offending substrates in the CNS with consequent improvement in motor behavior and notable extension of their life spans. As the therapy is necessarily invasive and chronic, we have evaluated the potential of substrate reduction therapy as an adjuvant therapy in the management of a subset of these neuropathic lysosomal storage disorders. Earlier preclinical studies have indicated that small molecule inhibitors of glucosylceramide synthase can be successfully deployed to reduce the frequency of enzyme infusions for treating the glycosphingolipidoses. While the orally available inhibitor (Genz-112638) that is presently tested in non-neuropathic Gaucher patients is incompatible for delivery to the CNS, we have explored other chemical scaffolds that may be more conducive to traversing the blood brain barrier. Oral administration of one such inhibitor (Genz-529648) into Sandhoff mice was effective in delaying the progression of the disease and extending their longevity. Hence, a combination of enzyme and substrate reduction therapies may be employed to optimally manage the CNS manifestations associated with a subset of the glycosphingolipidoses. Current efforts are directed at determining if these encouraging observations in the diseased mouse models are translatable to larger animals.