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Vol. 11 Supplement 1

November 2013


Lysosomal Storage Disorders: old diseases, present and future challenges

Andrés D. Klein, Ph.D. and Anthony H. Futerman, Ph.D.


Lysosomal storage diseases (LSDs), which are inborn errors of metabolism, encompass around 50 different inherited syndromes. Together, they have an incidence of 1/7000 newborns. LSDs are caused by deficiencies in lysosomal enzymes or transporters, resulting i n intra - l y s osomal buildup of under graded metabolites. Common features of LSDs include bone disease, organomegaly and central and peripheral nervous system degeneration. These diseas e s were f i r s t described i n the 1880s . Despite more than an hundred years of study of the genetic and molecular bases of LSDs, little is known about the events that lead from intralysosomal accumulation to the distinctive cell dysfunction and pathology that is characteristic of each disease. This review focuses on the main historical discoveries in LSD biology, from the original descriptions of their phenotypes, to animal models, including therapeutic strategies and challenges to treat this family of devastating diseases.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 59-63

Key Words: Ly s o s o m a l s t o r a g e d i s o r d e r s , lysosomes, animal models of disease, therapeutic approaches


Orphan Drug Development

Gregory M. Pastores, MD; Punita Gupta, MD


Comme r c i a l t rea tment f o r a l y sosoma l s tor a ge d i sorder ( L S D ; i . e . , Gauc h e r disease) became available in 1991 as a consequence of collaborative efforts between t h e N a t i o n a l I n s t i t u t e s o f H e a l t h a n d a biotechnology company, Genzyme Corporation, fostered by the Orphan Drug Act. (ODA, 1983) Other therapies were subsequently introduced for other LSDs (e.g., for Fabry disease) through ODA-driven incentives, as combined projects between academia and industry, facilitated by the Bayh-Dole Act (1980). Today, several enzyme therapies are available and other treatment o p t i o n s a r e a n t i c i p a t e d , i n c l u d i n g s m a l l molecular drugs which inhibit substrate synthesis or act as pharmacologic chaperones. Diseasespecific therapies has modified disease course to varying extents, and on-going data collection through registry/observational programs are in place to characterize both long-term safety and efficacy. Aspects of disease that remain challenging include those resulting from bone and brain involvement, which may necessitate novel therapeutic strategies. Issues related to high cost of therapy and access also remain to be addressed.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 64-67

Key Words: Lysosomal storage disease, animal model, enzyme deficiency, orphan drug act


Clinical Studies in Lysosomal Storage Diseases: Past, Present And Future

Pol F. Boudes, MD


Lysosomal storage disorders (LSDs) are made of over 40 diseases. Costly treatments have been developed. In this review, we consider the regulatory context in which LSDs studies are performed, and highlight design specificities and operational aspects. Orphan drug legislations in Europe and US were effective to stimulate LSDs drug development. However the flexibility of regulators to facilitate approval is inconsistent leading to worldwide differences in access to LSD treatments. Study designs are impacted because only few patients can be stud ied. Th i s implies L SDs treatments need to demonstrate a large efficacy e f f e c t . O t h e r w i s e t h e l e v e l o f e v i d e n c e i s difficult to demonstrate. While biomarkers could accelerate approvals, in LSDs none have been accepted as primary o u t c o m e o f e f f i c a c y. E n r i c h m e n t o f s t u d y population can increase the chance of success, e s p e c i a l l y w i t h c l i n i c a l o u t c o m e . Adaptive designs are challenging. Innovative methods of analysis can be used, notably us ing a patient as his/her own control and responder analysis. Other characteristics include extension phases and patient registries to further data collection. Few patients are available per centers and more centers need to be initiated in multiple countries. This impacts time-lines and budget. Fo r LSDs , development p r o g r am should b e individualized. Regulators flexibil ity will be essential to provide patients access to innovative treatments.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 68-76

Key Words: Lysosomal Storage Disorders, therapy, biomarkers , c l in ical markers , study design, orphan drugs


Oral Small Molecule Therapy for Lysosomal Storage Diseases

Neal J Weinreb, MD


Fo r m o r e t h a n 2 0 y e a r s , “ e n z y m e replacement therapy” (ERT) has been the prevalent treatment approach for lysosomal storage disorders (LSDs). Unfortunately, ERT, as currently administered, is ineffective for primary neuronopathic LSDs . For LSDs whose major disease burden is non-neurological, ERT efficacy is limited by uneven tissue distribution and penetration, immunological intolerance, and disturbed intracellular homeostasis associated with pers istent mutant enzymes that are not “replaced” by ERT. Many of these limitations might be circumvented by oral, low molecular weight pharmaceuticals that address relevant LSD pathophysiology and distribute widely in steady state concentrations in all cells and body tissues including the CNS. Two oral small molecule drugs (miglustat and cysteamine) are currently approved for clinical use and two (eliglustat and migalastat) are in advanced stage clinical trials. Several others are in early stages of clinical or pre-clinical i n v e s t i g a t i o n . T h i s art i c l e reviews current knowledge of small molecule treatment for LSDs including approaches such as substrate synthesis inhibition, pharmacological chaperones, and proteostasis modification.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 77-90

Key words: small molecule, lysosomal storage diseases, oral therapy, substrate, chaperone


Hematopoietic Stem Cell Transplant for Lysosomal Storage Diseases

Troy C. Lund, MD PhD FAAP


Hematopoietic stem cell transplantation (HSCT) for lysosomal storage diseases (LSD) has been performed for over 20 years. In that time, many advances have been made in understanding the unique pathophysiology of the various LSDs. We have also made advances in HSCT, part icularl y in the use of umbil ical cord blood as a stem cell source. The goal of HSCT has always been to correct the deficient lysosomal enzyme through the engraftment of enzyme replete donor cells that include cells of the hematopoietic system and it’s derivatives ( i.e. brain microgl ia). In those LSDs that are accompanied by some form of neuro-degeneration as part of their phenotype, one of the primary endpoints of performing HSCT is to slow or arrest the neurodegenerative process. As a general rule, earlier HSCT leads to improved outcomes since irreversible organ and tissue damage has had less t ime to occur. Mostly through trial and error we have learned which LSDs respond best to HSCT and which have shown minimal improvement after HSCT. Due to the rare nature of LSDs, this learning process is not complete. Even after two decades of performing HSCT for LSDs, many experiences are still being published as case reports. In recent years, the advent of enzyme replacement therapy for several of the LSDs offers new avenues for treatments that can be complemented by HSCT. In this review, we discuss what is currently known of HSCT related outcomes in the treatment of LSDs.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl 1): 91-98

Keywords : l y s o s o m a l s t o r a g e d i s e a s e , h e m a t o p o i e t i c c e l l t r a n s p l a n t , neurodegeneration, mucopolysaccharidosis


Gene Therapy for Lysosomal Storage Disorders

Nelson S. Yew PhD, Seng H. Cheng PhD


Lysosomal storage diseases (LSDs) are a group of single-gene disorders that have proven to be highly informative in revealing the merits of gene transfer as a technology platform. Over the past several years considerable progress has been made in delivering therapeutic genes to peripheral tissues as well as the central nervous system. The current leading vectors for direct genetic modification of target cells in vivo are derived from adeno-associated viruses (AAV) and lentiviruses. These vectors are capable of conferring widespread, robust, and sustained expression of a given gene in severa l mouse models of LSDs. Here we review recent progress using recombinant AAV and lentiviruses to treat various LSDs and the remaining challenges t o translate the results in mice to human patients.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 99-109

Key Words: gene therapy, viral vectors, mouse models, brain, primates, clinical trials


Legal and Regulatory Aspects of Orphan Drugs

Segev Shani, PhD1, MHA, MBA, Zohar Yahalom LLB2


Ra r e ( o r p h a n ) d i s e a s e s a re d e f i n e d a s diseases whose prevalence is significantly low. Many of these diseases are diagnosed at childhood by pediatricians. Rare diseases pose many obstacles for health care systems in general and patients specifically. As they are rare, they are less investigated, there is less knowledge a b o u t t h e d i s e a s e a n d l e s s p r o f e s s i o n a l s specia l izing in it. Furthermore, as for most diseases there is no specific treatment, diagnosis is not relevant. From industry perspective, as the market potential is small, there is no financial incentive to invest in developing treatments for rare diseases. Al l the above led patients, researchers and policymakers around the world to legislate specific laws designated to encourage and provide incentives for researchers and for the pharmaceutical industry to develop scientific and cl in ical knowledge as well as potenti a l treatments for these diseases. The objective of this article is to describe the initiation and current status of public health policy concerning orphan disease and drugs.

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 110-115

Key Words: o r p h a n d i s e a s e , o r p h a n d r u g , regulatory authority, orphan legislation, pricing and reimbursement


Orphan Drug Development and the Impact on Non-Medical Support Groups

Jeremy Manuel O.B.E1, Tanya Collin-Histed2


The Orphan Drug legislation in the United S t a t e s a n d l a t e r i n t h e E U h a s h a d a significant impact on patients worldwide who suffer from an orphan condition. Apart from providing statutory encouragement and incentives to pharmaceut ica l companies to develop therapeutic products it has resulted in the encouragement of patients to come together to form patient bodies to advocate on behalf of patients. Starting in a modest way patient groups have gained experience in working with clinicians and scientists and representing their members to companies and to healthcare providers in national European and global environments. This article describes the history and evolution of the patient body and the coming together of national patient groups through umbrella organisations which have proven to be a powerful advocate for pan European and global collaboration and humanitarian aid. I t also wil l review of some unintended consequences of the legislation

Ref: Ped. Endocrinol. Rev. 2013;11(Suppl1): 116-124

Key Words: O r p h a n D e s i g n a t i o n , P a t i e n t Organis a t i o n s : European Gaucher A l l i a n c e , Ly s o s o m a l S t o r a g e D i s o r d e r s ; I m p a c t o f Regulation



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