The Lysosome and lysosomal storage disorders (LSD)

1. The Lysosome and lysosomal storage disorders (LSD) Part III B Clinical profile of the LSDs Serge Melançon, MD February 2009

2. Prevalence of LSDs

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

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 bodily system • Symptoms vary in severity from relatively mild to severe somatic and rapidly progressive neurologic manifestations. • Even those without formal sub-types based on age of onset, affected organs/systems, and severity generally encompass a spectrum of clinical manifestations

7. "Red Flag" Symptoms

8. "Red Flag" Symptoms • While no single symptom is an LSD hallmark, several frequently present across enough of the disorders that they can 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 neurologic 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 Pompe Picnodysostosis Muscle waisting Hypotonia

16. Progression and outcome

17. Progression and outcome • The LSDs with neurologic involvement can often be the most severe, marked by rapid decline and high mortality rates • But generally, predicting LSD progression and outcome is challenging, especially in later-onset patients

18. Progression and outcome • A single 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. Progression and outcome 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 of LSDs

21. Prognosis of LSDs • Early identification and diagnosis is essential for appropriate management. • Early intervention is mandatory for the most serious and debilitating symptoms (particularly neurologic 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 (usually a geneticist) 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. Therapies for lysosomal storage disorders

24. Disease Management • For most LSDs, no disease-specific therapy is 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 biochemical cause of the disease

25. Disease-Specific Treatment Options • Hematopoietic stem cell transplant (HSCT) Healthy stem cells (from bone marrow or cord blood) are transplanted i.v. to the patient to provide new healthy cells that produce the missing enzyme. • Enzyme replacement therapy (ERT) A recombinant form of the deficient enzyme is infused i.v. at definite intervals.

26. 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.

27. Bone marrow transplant • First attempted in the 1980s and has been most 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

28. Enzyme Replacement Therapy

29. Enzyme Replacement Therapy • R&D began in the mid-1960s, and by the 1980s clinical trials were underway. • In the early 1990s, advances in recombinant DNA manufacturing enabled enzyme production in quantities large enough for commercial development

30. Enzyme Replacement Therapy • The first ERT for Gaucher type I went on the market in 1991 • ERT is a treatment option for 4 LSDs Gaucher Type I, Fabry, MPS I (Hurler/Scheie) and MPS II (Hunter) • And will soon be for 3 more LSDs Pompe (GSD type II) and MPS VI (Maroteaux-Lamy)

31. Current cost of ERT (US$)

32. 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

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

34. Zavesca inhibits glucosylceramide synthase, the first enzyme responsible for glycosphingolipid (GSL) synthesis.

35. Research Efforts for LSD

36. Research Efforts for LSD Treatment Options • Both ERT and HSCT have limited efficacy on neurologic symptoms, since the large enzyme molecules introduced intravenously cannot penetrate the blood-brain barrier • ERT development continues to face challenges, such as difficulties targeting the affected cell

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: • Enzyme enhancement therapy which attempts to stabilize faulty enzymes in LSDs caused by enzyme malfunctions (rather than total deficiency)

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 presence (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. THANK YOU AND HAVE A NICE DAY