The Lysosome and lysosomal storage disorders (LSD)

1. The Lysosome and lysosomal storage disorders (LSD) Part 3A Clinical profile of the LSDs Serge Melançon, MD February 2010

2. PREVALENCE The lysosomal diseases are a group of more than 50 inherited metabolic disorders with a total incidence of 3-4 cases per 10,000 newborns.

3. Sandoff 2% Gaucher 14% Gm1 Gangliosidosis 2% Mucolipidosis II/III 2% Niemann Pick A/B 3% MPS I H/S 9% Maroteaux-Lamy 3% Niemann Pick C 4% Sanfilippo B 4% Metachromatic Leukodystrophy 8% Tay-Sachs 4% Cystinosis 4% Sanfilippo A 7% Morquio 5% Fabry 7% Pompe 5% Krabbe 5% Hunter 6% (For Australia1980-1996; Meikle et al., JAMA 281;249-254 Lysosomal Storage Disorders MPS 34%

4. PRESENTATION AND PROGRESSION • While early onset pediatric forms of LSD present with classical and rapidly progressive clinical courses, • Heterogeneous and unusual clinical presentations are the hallmark of common adult forms of LSD

5. PRESENTATION AND PROGRESSION • Heterogeneous presentation across the LSD categories and often even within a single disease • Wide clinical variability according to different types of substrate stored and locations of storage • Clinical manifestations tend to be progressive, as more waste substrate accumulates over time.

6. PRESENTATION AND PROGRESSION • As a group, LSDs affect nearly every organ and system • Symptoms vary in severity from relatively mild to severe somatic and rapidly progressive neurological manifestations CLINICAL SPECTRUM

7. "Red Flag" Symptoms

8. "Red Flag" Symptoms • While none is an LSD hallmark, several present across enough of the disorders to raise a physician's suspicion and prompt further investigation. • LSD symptoms often present in clusters, so the appearance of more than one of these is even more suggestive

9. "Red Flag" Symptoms • Coarse facial features (sometimes with macroglossia) • Corneal clouding or related ocular abnormalities • Angiokeratoma • Umbilical / inguinal hernias • Short stature • Developmental delays • Joint or skeletal deformities • Visceromegaly (especially liver and spleen) • Muscle weakness or lack of control (ataxia, seizures, etc.) • Neurologic failure/decline or loss of gained development

10. Coarse facial features Corneal clouding Umbilical hernia

11. Skeletal Abnormalities Gaucher MPS I

12. Joint deformities Angiokeratoma Visceromegaly

13. "Red Flag" Symptoms • Particularly noteworthy are the following signs: • Loss of motor skills, • Increasing dementia or behavioural abnormalities, • Muscular or neurological deterioration, • That suggest a progressive / degenerative disorder.

14. Aspartylglycosaminuria Cystine crystal deposits Kyphosis Cystinosis Lymphadenopathy Ataxia Hypertonia Krabbe Disease Farber

15. Retinitis pigmentosa Strabismus Cherry red spot Neuronal ceroid lipofuscinosis Infantile Sialic acid SD Small jaw GM2 Gangliosidosis Cardiomegaly Macroglossia Picnodysostosis Pompe Muscle waisting Hypotonia

16. PROGRESSION AND OUTCOME

17. PROGRESSION AND OUTCOME • Predicting LSD progression and outcome is challenging, especially in later-onset patients • LSDs with neurological involvement are often the most severe with rapid decline and high mortality rates

18. PRESENTATION AND PROGRESSION • One disease is often associated with several different gene mutations, which may account in part for the disease's clinical heterogeneity. • However, the very same mutations may result in quite different outcomes in different patients and genotype-phenotype correlations are not always consistent

19. PRESENTATION AND PROGRESSION Other factors can also influence outcome: • residual enzyme activity versus complete deficiency, • age of diagnosis and of onset of treatment or supportive care • environmental influences; • unknown genetic and epigenetic factors

20. PROGNOSIS

21. PROGNOSIS • Earlydiagnosis is essential for more diverse treatment options • Early intervention is mandatory for the most serious and debilitating symptoms, particularly neurological and skeletal • Once established these often will not respond to even disease-specific therapies

22. DISEASE MANAGEMENT • Requires a multidisciplinary team approach, with a lead physician directing care and referring to other specialists as necessary • Treatment options vary across the LSDs • Often various therapies and/or care will be offered

23. The Treatment Team Pediatrician Ophthalmologist Surgeon Pulmonologist Otorhinolaryngologist InterventionalGeneticist Cardiologist Orthopedist Neurologist Anesthesiologist Dentist Gastroenterologist Genetic Counselor

24. DISEASE MANAGEMENT • For most LSDs, no disease-specific therapy is currently available • Clinical manifestations can only be addressed through palliative measures such as physical therapy, dialysis or surgery • These methods can be effective in managing symptoms, but they do not affect the pathophysiology of the disease

25. DISEASE-SPECIFIC TREATMENT OPTIONS

26. DISEASE-SPECIFIC TREATMENT OPTIONS • Hematopoietic stem cell transplant (HSCT) Healthy stem cells (from bone marrow or cord blood) are transplanted i.v. to provide normal enzyme producing cells to the patient • Enzyme replacement therapy (ERT) A recombinant form of the deficient enzyme is infused i.v. at definite intervals

27. DISEASE-SPECIFIC TREATMENT OPTIONS • Enzyme enhancement therapy (EET) Misfolded enzyme is stabilized during its synthesis by the use of small chemical chaperones • Substrate reduction therapy (SRT) The rate of production of the substrate is slowed by drug therapy

28. Hematopoietic stem cell transplant • First attempted in the 1980s and mostly used for MPS I • Positive results when performed early in a disease's course, despite its challenges and risks • transplant failure or rejection • toxicity of the conditioning regimen • difficulty finding a good donor match • Improved chance for success in newborns with naturally suppressed immune systems

29. ENZYME REPLACEMENT THERAPY

30. ENZYME REPLACEMENT THERAPY • R&D began in the mid-1960s • Clinical trials by the 1980s • Advances in recombinant DNA manufacturing in the early 1990s enabled enzyme production in quantities large enough for commercial development

31. ENZYME REPLACEMENT THERAPY • The first ERT went on the market in 1991 for Gaucher type I • ERT is a treatment option for 6 LSDs • Gaucher Type I • Fabry • MPS I (Hurler/Scheie) • MPS II (Hunter) • Pompe (GSD type II) • MPS VI (Maroteaux-Lamy)

32. CURRENT COST OF ERT

33. SUBSTRATE REDUCTION THERAPY • SRT was introduced in 2002 for Gaucher Type I patients where ERT is not an option • Further clinical studies are in progress for • Fabry disease • GM2-gangliosidoses (Tay-Sachs, Sandhoff, GM2 activator disease) • Niemann-Pick type C

34. After SRT Reduced level of glucosylceramide helps relieve the burden on the residual glucocerebrosidase. Before SRT Glucosylceramide exceeds capacity of residual glucocerebrosidase activity.

35. RESEARCH EFFORTS FOR LSD

36. RESEARCH EFFORTS FOR LSD TREATMENT OPTIONS • Both HSCT and ERT have limited efficacy on neurological symptoms, since the large enzyme molecules cannot penetrate the blood-brain barrier • ERT development continues to face challenges, such as difficulties targeting the affected cell in remote tissues, such as joint, bone and brain

37. RESEARCH EFFORTS FOR LSD TREATMENT OPTIONS • Small molecule drugs can generally be administered orally and cross the blood-brain barrier where they act as pharmacologic "chaperones” to enable deficient proteins • Enzyme enhancement therapy attempts to stabilize misfolded protein and restore enzyme activity

38. RESEARCH EFFORTS FOR LSD TREATMENT OPTIONS • Substrate synthesis inhibition therapy • attempts to block a step in the production of waste to minimize the accumulation • may be most effective in patients with some residual enzyme activity (rather than total deficiency) and as an adjunct to other treatments (such as ERT)

39. RESEARCH EFFORTS FOR LSD TREATMENT OPTIONS • Gene therapy • involves replacing the patient's mutated gene with a normal copy so proper enzyme production can occur • still only in preclinical (animal) studies, and much research is needed, especially in identifying appropriate vectors for gene delivery

40. GENE THERAPY

41. ANY BURNING QUESTION AT THIS POINT?

42. How about an exam question?

43. Biochemical and Cellular basis of lysosomal storage disorders • Most mutations result in the delivery of a defective enzyme with a reduced catalytic activity to lysosomes • Another (activator) protein required for optimal hydrolase activity is defective or absent • A mutation that causes misfolding results in defective transport of a lysosomal hydrolase out of the endoplasmic reticulum • Alternatively, defective transport of a lysosomal hydrolase out of the ER occurs because a multi-enzyme complex that is required for transport cannot form (Cathepsin A / sialidase / -galactosidase )

44. Biochemical and Cellular basis of LSDs… • In the Golgi, defective glycosylation could result in an enzyme with reduced catalytic activity • Alternatively, defective glycosylation with mannose-6-phosphate in the Golgi could produce an enzyme that cannot reach lysosomes • Defects in other transport steps from the Golgi could also lead to an LSD • Defects in integral lysosomal membrane proteins with transporter roles 9 Defects in proteins that are involved in other vital regulatory events of lysosomal function (LAMP2, lysosomal associated membrane protein 2)

45. Biochemical and Cellular basis of LSDs 1 catalytic activity 2 activator 3 misfolding 4 multienzyme complex 5 glycosylation 6 M-6-P targetting 7 other transport steps 8 membrane transporters 9 membrane regulators Futerman AH & van Meer G (2004) 5:554-565