101. Regulation and review of small clinical trials

Anne Pariser, Food and Drug Administration

The Orphan Drug Act (ODA) was enacted in 1983 to promote the development oftreatments for rare diseases, predominantly through financial incentives. The ODAhas been highly successful, and has resulted in almost 2000 promising compoundshaving been designated as orphan products by the US FDA, and over 300 of these havereceived US marketing approval, which includes 43 designations for products beinginvestigated for the treatment of LSD, 9 of which have received marketing approval.Although the ODA has been successful in stimulating research and development ofproducts for LSD, considerable need for new treatments remain.

Substantial challenges exist for the clinical development of new treatments forLSD beyond financial concerns. LSD are amongst the rarest of orphan disorders withfew patients available for study, usually necessitating multi-center trials and interna-tional collaboration. LSD are also a highly heterogeneous collection of diseases withdiverse clinical presentations and progression, and substantial phenotypic variabilitywithin disorders, necessitating individualized approaches to development, trialdesign and statistical considerations, and selection of outcome measures and popula-tions for study, all of which contribute to special challenges for the regulation andreview of these treatments. Directions for future study include: (1) the use of bio-markers for the diagnosis, monitoring, and assessment of disease; (2) additional dis-ease characterization through natural history studies; (3) exploration of new outcomemeasures in clinical trials, such as imaging modalities, surrogates, and standardizedclinical instruments; (4) immune tolerizing regimens; and (5) improved compart-ment/tissue/cellular targeting of therapies.

doi:10.1016/j.ymgme.2009.10.118

102. Update on lysosomal diseases research supported by The Eunice KennedyShriver National Institute of Child Health and Human Development (NICHD):From basic science to newborn screening and therapeutic interventions

Melissa Parisi, Tiina K. Urv, Mary Lou Oster-Granite, James W. Hanson, R. RodneyHowell, Eunice Kennedy Shriver National Institute of Child Health and HumanDevelopment, National Institutes of Health, Bethesda, MD, USA

Lysosomal diseases (LSD) represent a heterogeneous group of disorders with neu-rological and multi-system impairment. Understanding the etiology and natural historyof these disorders, developing methods for early diagnosis, and developing treatmentsto reduce the burden of disease are goals that span the mission of the NIH. The NICHDsupports research to promote progress in the field of LSD including basic science inves-tigations into the mechanisms of immune tolerance in Pompe disease and transport ofenzymes across the blood–brain barrier. Several NICHD-funded investigators aredeveloping novel gene therapy and enzyme replacement approaches for Globoid-CellLeukodystrophy and other LSD. NICHD also funds research to develop LSD-specificassays utilizing dried bloodspots for applications such as newborn screening. Recently,NIH support has been provided to two Rare Disorders Clinical Research Consortia, forLSD and for Sterol and Isoprenoid Disorders, and a 5-year contract was awarded tothe American College of Medical Genetics to create a Newborn Screening TranslationalResearch Network Coordinating Center to provide infrastructure support to investiga-tors who validate screening technologies, establish long-term follow-up protocols,and develop therapeutic interventions for screenable disorders including LSD. TheNICHD plans to support a workshop on ‘‘Advances and Challenges in Understandingand Treating Lysosomal Disorders’’ based on the recognition that early detection andeffective treatment in newborns and infants is critical to reduce long-term morbidityand mortality. NICHD will continue to support innovative LSD research in the future,and is particularly interested in development of optimal screening technologies andtheir comparative effectiveness, long-term follow-up, and clinical interventions.

doi:10.1016/j.ymgme.2009.10.119

103. Screening for Fabry and Pompe disease in high risk populations by enzymeassay of dried blood spots

Oliver Parks, Heather Church, Karen Tylee, Alan Cooper, Willink Unit, Genetic Medicine,St. Marys Hospital, Manchester M13 9WL, UK

Fabry and Pompe disease can present with atypical or late onset symptoms. Thesedisorders are due to deficient activity of the lysosomal enzymes a�galactosidase Aand b�glucosidase, respectively. Atypical Fabry patients may present with left ven-tricular hypertrophy, isolated kidney disease or unexplained stroke. Late onset Pompedisease normally presents with unexplained, progressive muscle weakness. In an at-tempt to identify variant forms of these disorders, dried blood spots have been col-lected from renal, cardiac, neurology and neuromuscular clinics. Once collected,

dried blood spots can be stored desiccated at �20 and shipped in batches, at ambienttemperature, by first class post.

Once received, dried blood spots were stored desiccated at �20 until analysis(within one working week). Three-millimeter spots were punched from the cards into96 well plates and enzyme proteins extracted into detergent by shaking plates on anorbital shaker. a�galactosidase A and b�glucosidase activities was measured usingfluorimetric substrates based on 4-methylumbelliferone. Assays for the two enzymeswere validated by assay of 100 control samples and also samples from known affectedpatients. Three hundred and eighty-three samples were received from patients at riskfor Fabry and 58 for Pompe. Eight patients were identified with Pompe disease includ-ing three infantile onset patients from the Middle East. Two male Fabry patients wereidentified by this procedure. Results were confirmed by enzyme assay in other tissuesand genotyping.

doi:10.1016/j.ymgme.2009.10.120

104. Alpha-galactosidase A enzyme replacement using the salivary glands asendogenous therapeutic production sites

Michael Passineau, Katie Nega, Rachel Paul, Laurie Machen, Lee Zourelias, RaymondBenza, Allegheny-Singer Research Institute

Enzyme Replacement Therapy (ERT) has transformed the treatment of a variety oflysosomal storage disorders (LSD) but current ERT practice, involving bi-weekly infu-sions, still suffers drawbacks. Therefore various gene therapy approaches have beenexplored to allow endogenous production of therapeutic enzymes such as alpha-galactosidase A (GLA) with the hope that a constant ‘‘trickle’’ of enzyme into the cir-culation might be preferable to bi-weekly bolus injections.

The salivary glands are an intriguing gene therapeutic biosynthesis site, and arecapable of secreting gene products into the blood via an endocrine secretory pathway.In this study, we hypothesized that GLA expressed in the salivary gland would enterthe systemic circulation and be taken up by target organs in the GLA knockout mouse.2E10 viral particles of an Adenovirus expressing GLA were administered unilaterallyto one submandibular gland in the GLA knockout mouse via catheterization of thesubmandibular duct. Four days later, mice were sacrificed and saliva, plasma, kidney,brain and liver were collected, homogenized and subjected to a GLA enzymatic activ-ity assay. Tissues from wild-type littermates served as normal, untreated controls.

GLA activity in treated knockout animals was substantially and significantly ele-vated in plasma, kidney, liver, and brain relative to both untreated knockout animalsand untreated wild-type animals. GLA activity in saliva was identical across allgroups. These studies demonstrate the initial feasibility of expressing GLA in the sal-ivary glands to effect systemic enzyme replacement in a mouse model.

doi:10.1016/j.ymgme.2009.10.121

105. Gaucher disease: In need of foster care?

Gregory Pastores, Carol Fisher, NYU School of Medicine, NY, USA

Gaucher disease (GD) was an orphan disorder that had been successfully treatedby enzyme therapy using imiglucerase. The current shortage in imiglucerase supplyhas created an unusual situation, which has forced a re-examination of treatment par-adigms for this lysosomal storage disorder. As treatment interruptions had not beensystematically examined in a large cohort of patients, the current situation has pro-vided us with an opportunity to assess outcomes for at least four groups of patients:(1) those whose treatment will continue on imiglucerase, on either the same dose andfrequency, or an alternative regimen; (2) those who elect to be monitored off therapy;and those who consider a switch to either (3) an oral option; that is (a) miglustat or(b) GENZ112638 or (4) a different enzyme formulation. Currently, the NYU Gaucherdisease program follows 300 GD patients, including those enrolled in theGENZ112638 and pr-GCB (Protalix) study. Data on the latter patients will not be dis-cussed. Our presentation will describe the decision process and choices made by thepatients, to either be managed conservatively until imiglucerase supply is restored orswitch to an alternative option. Outcome data, covering the period of July 2009 to Jan-uary 2010, for these different groups of patients will also be discussed.

doi:10.1016/j.ymgme.2009.10.122

106. Longitudinal study of cognition in subjects with Niemann–Pick disease, type C

Marc Pattersona, Tanya Browna, Rebecca Vauriob, Nicole Yanjaninc, Forbes Porterc,aMayo Clinic, Rochester MN, USA, bThe Hugo W. Moser Research Institute at KennedyKrieger, Inc., Baltimore, MD, USA, cNICHD, NIH, DHHS, Bethesda, MD, USA

Abstracts/Molecular Genetics and Metabolism 99 (2010) S8–S41 S29