effect of low-dose celecoxib on smn2 in patients with spinal muscular atrophy

Conditions: Spinal Muscular Atrophy (SMA)

Summary: several factors make the use of celecoxib in human sma patients appealing including: 1) low-dosing required for potential therapeutic effect (the corresponding dose in humans is much lower than that commonly used in adults and children with; 2) favourable side effect profile of this drug (particularly at the dosing required); 3) the fact that celecoxib crosses the blood brain barrier and 4) demonstration of efficacy in a genetically and pathophysiologically faithful animal mode. the investigators therefore believe that celecoxib is a promising disease modifying therapy for sma.

this is a pilot, open-label, dose-response study in patients with sma type ii or iii. all patients will be treated at each dose of once daily celecoxib (40, 80 and 160 mcg/kg) for a period of two weeks, for a total of 6 weeks (42 days) of treatment.

Eligibility criteria:
inclusion criteria: 1. confirmed genetic diagnosis consistent with sma that can include: smn1 gene deletions, rearrangements and/or mutations 2. sufficient clinical information enabling the patient to be classified as either sma type ii or iii. (patients with sma type ii are defined as having achieved the motor milestone of sitting independently for \> 30 seconds but not having been able to stand or walk unsupported. patients with sma type iii are defined as having achieved the motor milestone of standing or walking independently). 3. confirmed genetic test result indicating number of smn2 gene copies 4. age \> 2.0 years old at screening 5. patients weighing at least 12 kg at screening 6. stable dosing (for at least 3 months) of medications that may affect function of muscle, nerve and/or neuromuscular transmission or gene expression (including but not limited to: coenzyme q10, creatine monohydrate, nutritional supplements, oral salbutamol, valproic acid, sodium phenylbutyrate, hydroxyurea) 7. written informed consent obtained from patient and/or parents or legal guardians exclusion criteria: 1. clinical presentation and/or genetic testing that is not consistent with sma type ii or iii 2. inability or unwillingness to swallow celecoxib suspension 3. major surgery (scoliosis repair, g-tube insertion) within past 3 months 4. known hypersensitivity or allergy to celecoxib (including asthma, urticaria and/or other allergic symptoms resulting from prior celecoxib ingestion) or its excipients, or other nsaids (non-steroidal anti-inflammatory drugs) including asa (acetylsalicylic acid) 5. known hypersensitivity or allergy to ora-blend® or its excipients 6. demonstrated allergic-type reaction to sulfonamides 7. celecoxib use within 2 weeks prior to screening visit 8. known cardiac (ie. uncontrolled heart failure, cerebrovascular bleeding, hypertension requiring the use of anti-hypertensive medication), hepatic (i.e. severe liver impairment or active liver disease), gastrointestinal (i.e. inflammatory bowel disease; active gastric/duodenal/peptic ulcer disease; or active gastrointestinal bleeding), hematologic (ie. thrombocytopenia defined as platelets \< 50,000 or hemophilia), respiratory or renal disease(i.e. severe renal impairment defined as creatinine clearance \< 30 ml/min) wherein the use of nsaids is contraindicated as per product monograph dated 03 march 2015. 9. concurrent use of medication contraindicated with celecoxib use (including but not limited to, warfarin, fluconazole, lithium, hydrochlorothiazide) 10. female who is pregnant or breast feeding 11. female of child-bearing potential who is sexually active and unwilling or unable to use at least one form of highly effective and one effective method of birth control. 12. patients participating in any pharmaceutical clinical trial (with active agent) that could impact with the results of this study 13. inability or refusal to provide informed consent