Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

-INCLUSION CRITERIA:

1. Aged greater than or equal to 18 and less than or equal to 60 years old at time ofenrollment, either gender, and any ethnicity.

2. Diagnosis of NPC1 based upon one of the following:

• Two NPC1 mutations;

• Positive filipin staining and at least one NPC1 mutation;

• Vertical supranuclear gaze palsy (VSNGP) in combination with either:

• One NPC1 mutation, or

• Positive filipin staining and no pathogenic NPC2 mutations.

3. Patients with at least one neurological manifestation of NPC1. For example, but notlimited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia,dystonia, seizures, dysarthria, or dysphagia.

4. A patient s cultured skin fibroblasts when treated with 10 M Vorinostat must exhibit areduction in the filipin lysosomal storage organelle ratio equivalent to 75% of theresponse measured in NPC1 positive control fibroblasts.

5. Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-up.

6. If taking miglustat, the patient must have been taking a constant dose of themedication for no less than three months prior to baseline evaluation and must bewilling to maintain that dose level for the duration of the trial.

7. Willing to discontinue all non-prescription supplements, with the exception of anage-appropriate multivitamin.

8. Women of reproductive age must be willing to use an effective method of contraceptionfor the duration of the trial.

9. Willing to participate in all aspects of trial design including serial blood and CSFcollections.

EXCLUSION CRITERIA:

1. Aged below 18 or above 60 years of age at enrollment in the trial.

2. Severe manifestations of NPC1 that would interfere with the patient s ability tocomply with the requirements of this protocol.

3. Neurologically asymptomatic patients.

4. Patients who have received any form of cyclodextrin or an HDACi in an attempt to treatNPC1.

5. History of hypersensitivity reactions to Vorinostat or components of the formulation.

6. Pregnancy or breastfeeding at any time during the study.

7. Patients with suspected infection of the CNS or any systemic infection.

8. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 permicroliter.

9. Thrombocytopenia defined as a platelet count less than 75,000 per microliter, or ahistory of greater than or equal to grade 2 thrombocytopenia (50,000-75,000platelets/microliter).

10. Prior use of anticoagulants or history/presence of a bleeding disorder.

11. Hepatic laboratory parameters (aspartate aminotransferase (AST), alanineaminotransferase, (ALT)) greater than four-times upper limit of normal.

12. Presence of anemia defined as two standard deviations below normal for age and gender.

13. Serum creatinine level greater than 1.5 times the upper limit of normal.

14. Hematuria (greater than15 RBC/mcL or positive hemoglobin). This exclusion criteriawill not apply to a female currently menstruating who has no history of renal diseaseor other evidence of renal impairment (eg hypertension, serum creatinine above upperlimit of normal, history of renal disease). Urinalyis will be repeated after menseshas ended and drug discontinued if hematuria persists. Efforts will be made to avoidmenses in scheduling the initial admission.

15. Proteinuria (1+ protein on urinalysis) Patient will not be excluded if urineprotein/creatinine ratio is normal or if classified as benign by either patient'sprimary medical provider or upon obtaining a nephrology consult.

16. Serum potassium or Magnesium outside of the normal laboratory range prior toinitiation of vorinostat therapy.

17. Diabetes or a fasting glucose greater than 106 mg/dl.

18. Active pulmonary disease, oxygen requirement or clinically significant history ofdecreased blood oxygen saturation, pulmonary therapy, or requiring active suction.

19. Patients with uncontrolled seizures per either of the criteria below.

20. Unstable frequency, type or duration of seizures. Quantified by a seizure logover the two months prior to enrollment.

21. Patients requiring antiepileptic medication changes (other than dose adjustmentsfor weight) in the two months prior to enrollment, or requiring three or moreantiepileptic medications to control seizures.

22. Use of another HDAC inhibitor or compounds with established HDAC inhibitory activity,including valproic acid, unless discontinued at least 2 months prior to enrollment.

23. History of a thromboembolic event (such as DVT or Pulmonary embolism).

24. Patients, who in the opinion of the investigators, are unable to comply with theprotocol or have specific health concerns that would potentially increase the risk ofparticipation.