1. Hedy Smith MD, PhD Tufts Medical Center, Boston CMPAA 2016

2. What is Sickle Cell Disease? A genetic disease that alters hemoglobin in red blood cells A – T base pair substitution in codon 6 th of  globin gene Glutamic acid to Valine substitution Sickle Cell Disease is transmitted from both parents (silent carriers) Onset of symptoms is in childhood (around 6 months of age)

3. Sickle Cell Disease A family of disorders of variable severity Hb SS (sickle cell anemia / SCA) HbSC Hb S  thalassemia Hb SE Hb SD / O Arab Hb SS with hereditary persistence of fetal hemoglobin A number of genes influence the Hb S  globin gene Haplotypes SNPs

4. History of Sickle Cell Anemia (SCA) J. B. Herrick. Describes a young black male from the island of Grenada, who suffered from chronic hemolytic anemia with jaundice (Arch. Int. Med. 6: 517- 521, 1910).

5. Epidemiology Epidemic – a Global Health problem! “ We’ve known for 50 years what causes sickle cell disease. Where’s the cure?” No funding for SCD Globe News – Boston 2016

6. SCD around the World W. Africa: >120,000 babies born annually with SCD Jamaica: 1:10 individuals with trait; 1:150 births with SCD Brazil: 1:35 with trait, 1:1000 with SCD US: 1:500 with SCD; >90,000 affected

7. Cause of Illness in SCD Deoxygenation of sickle hemoglobin Globin chain precipitates in red cells Loss of solubility Red cell shape change Increased blood viscosity Blood vessel occlusion

8. Inflammation in Sickle Cell Disease Increase in white blood cells Increase in blood platelets Increased risk of blood clots Damage to the blood vessel (vasculopathy) Stroke Eye disease (retinopathy) Lung disease (pulmonary hypertension) Heart disease Kidney disease

9. Manifestations of Sickle Disease Anemia - red cell hemolysis Pain!! Organ ischemia & injury Death

10. Acute Complications of SCD Pain crisis – blood vessel occlusion with acute severe pain in bones Acute chest syndrome (ACS) Low blood oxygen (SO 2 <95%) Shortness of breath Fever (Temp >101°F) Abnormal chest X-Ray (looks like pneumonia) Risk of death Aplastic crisis (due to Parvo B19 infection) Splenic sequestration

11. Acute Complications of SCD Infections – loss of spleen function Urinary tract infections / pyelonephritis Pneumonias Osteomyelitis (100x more common than normal) Blood Clots (thrombosis) – prevalence 25%

12. Chronic Complications of SCD Pain Avascular necrosis of hips, shoulders Gallstones Jaundice Priapism Leg Ulcers Kidney Disease Stroke / eye disease (retinopathy) Headaches Lung & Heart disease Iron overload and alloimmunization due to blood transfusions

13. Management of SCD

14. Focus on Preventative care Neonatal Screening Programs – Jamaica, Brazil, US, Europe Will decrease mortality in children Identification of gene in families Family Education & Counselling Seek immediate medical care for fevers and breathlessness Prompt attention and intervention for sickle pain flares

15. Prevention Program Avoid extremes of temperature that trigger sickle crises Hydration – very important Healthy diet Avoid tobacco and illicit drugs Moderate exercise Weight management Good sleep habits Prompt medical attentions for fevers, chills, cough Compliance with medications – Folic acid, Hydroxyurea

16. Health Maintenance in SCD Antibiotic prophylaxis in childhood is mandatory TCD in children to determine risk of stroke Screening for neurocognitive impairment cause by silent strokes – validates patient concerns advocate for reasonable accommodations in schools and work place Screening for depression and anxiety Annual eye exams – treat retinopathy before blindness Heart ultrasound (ECHO) – pulmonary HTN, heart disease Vaccinations (Hepatitis B, Haemophilus influenza, Meningococcus, Pneumococcal, HPV) Dental care (aseptic pulp necrosis) – fluoride rinses

17. Health Maintenance in SCD Screen for iron overload - annual serum ferritin measurements chelation therapy if ferritin >1500 Chelators Deferoxamine (SQ) Exjade (oral) Jadenu (oral) Deferiprone (oral; iron overload in the heart)

18. Indications for RBC transfusion in SCD Transfuse for disease complications Stroke Acute retinal vessel occlusion Acute Chest Syndrome Organ failure (e.g. hepatic congestion, kidney injury) Surgery with general anesthesia Symptomatic severe anemia Inappropriate to transfuse for chronic steady state anemia uncomplicated pain episodes uncomplicated pregnancy minor surgeries done under local anesthesia

19. Recognize Sleep Disorders Screen for Obstructive Sleep Apnea (OSA) Screen for and treat concurrent Asthma

20. Reproductive Health in SCD Puberty is often delayed by 1.5 – 2 years Menstruation may be associated with pain flares – often need to induce menstrual arrest Contraception should be addressed & pregnancies counselled and planned - high risk! Screening of partners for sickle and other abnormal hemoglobin traits Discontinue Hydroxyurea ahead of pregnancy (birth defects) Increased risk of miscarriages Increased risk of pre-eclampsia and pre-term deliveries Risk of maternal mortality Growth retardation of fetus (small birth weights) High risk obstetrician

21. Therapeutic Landscape - Where are we? Can we target the complex pathophysiology of sickle disease with drug(s)? Can we contemplate cure for severe SCD?

22. Targeting Red Cell Sickling Enhance Fetal Hemoglobin production Hydroxyurea dosed @ 25mg/kg/d or MTD NIH guidelines - use in children @ 9months TWiTCH trial – HU reduced risk of stroke in children (increased blood flow) Decitabine Vorinostat Butyrates (HQK-1001)

23. Therapy for SCD Reducing Red Cell Destruction (Hemolysis) GBT-440 – Phase 1/2 Single daily oral dose Drug that enhances hemoglobin affinity for oxygen

24. Targeting Inflammation in SCD Antibodies to Selectins SelG1 (P-selectin antibody) Rivapansel – pan selectin (Phase III study ongoing) Regadenoson NKTT120 (anti-iNKT) Statins (Atorvastatin) Omega -3 Prasgruel – clinical trial failed

25. Gene Therapy in SCD Current Clinical Trial: BM CD34 + from SCD patients are transduced ex-vivo with the Lenti/βAS3- FB lentiviral vector. Gene engineered The transduced cells are then infused into the patient.

26. Bone Marrow Transplant in SCD NIH Experience – ablating diseased bone marrow and replacing it with stem cells from HLA matched sibling donor NIH: >40 adult patients transplanted; ~80% with full engraftment, no graft rejection, no fatalities {JAMA 2014;312(1), 48-56} Thousands now transplanted world-wide (adults & children), 94% survival; some >20 years "Our patients have had a remarkable change in their lives," said John F. Tisdale, M.D., the trial’s principal investigator in the NIH Molecular and Clinical Hematology Branch. "They are no longer being admitted to the hospital for frequent pain crises, they have been able to stop chronic pain medications, go back to school and work, get married and have children."

27. Sickle Cell Disease: NIH Health Information CONTACT US NIH Office of Communications and Public Liaison Building 31, Room 5B64 Bethesda, MD 20892-2094 nihnewsinhealth@od.nih.gov nihnewsinhealth@od.nih.gov Tel: 301-402-7337

28. Hope ! Thank You! Hope by Nazaire