Integrative Medicine and Experimental Pharmacogenomic Therapy in a Child with Niemann-Pick Disease (NPD), Type A


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A 34-month female with Niemann-Pick Disease, Type A (NPD-A) is presented. NPD-A is a rare autosomal recessive, hereditary lysosomal storage disease caused by reduced acid sphingomyelinase (ASM) activity. Reduced sphingomyelinase activity resulting in impaired sphingomyelin turnover leads to cellular lipid and lysosomal storage (foam cells), hepatosplenomegaly, delay and loss of developmental milestones, and degenerative neurologic deficits. Death occurs in infancy or early childhood, with the usual life span being 2-3 years. No effective treatment for NPD-A is known, although bone marrow transplantation and enzyme replacement therapy with ASM have been attempted. [Both have been tried for NPD-B, but I do not know if either of these techniques have been tried for NPD-A. This is true that no successful treatment has been demonstrated for humans with NPD-A, yet the Genzyme studies using adeno viruses were successful for mice.
See <>. Stem cell and gene therapy research is being investigated in animal models. This child is known to have an unusual stop-codon mutation. Aminoglycosides have been found in animal and small-scale human studies to cause read-through in translation effectively skipping the “stop-codon” and are in clinical trials in other genetic diseases with similar mutations. It was hypothesized that gentamicin would cause read-through in translation in this patient, and thereby increase production of acid sphingomyelinase. After presentation to the Ethics Committee of Lucile Salter Packard Children’s Hospital at Stanford University, the child was treated with an experimental protocol using intranasal gentamicin. This is the first case of NPD-A in which this has been tried.

This patient has also been treated with Traditional Chinese Medicine including acupuncture and botanicals, massage therapy, nutritional measures, homeopathy, energy healing and compassionate intention in an Integrative Medicine approach. Disease characteristics, clinical features and course will be described.

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Integrative Medicine and Experimental Pharmacogenomic Therapy in a Child with Niemann-Pick Disease (NPD), Type A

  1. 1. Integrative Medicine and Experimental Pharmacogenomic Therapy in a Child with Niemann-Pick Disease (NPD), Type A Sylvestre Quevedo, MD Osher Center for Integrative Medicine University of California School of Medicine San Francisco, California, USA Center for Integrative Medicine San Jose, California, USA Sophia’s Garden Foundation Scientific Advisory Board Palo Alto, California, USA Collaborator: Richard Ellson, Chair, Scientific Advisory Board, Sophia’s Garden Foundation
  2. 2. Incidences of LSD
  3. 3. Background of NPD <ul><ul><li>Types A and B NPD — two forms of same disease caused by mutations in gene for acid sphingomyelinase (ASM) </li></ul></ul><ul><ul><li>Results in reduced ASM activity in cellular lysosomes leading to sphingomyelin storage (lysosomal storage) </li></ul></ul><ul><ul><li>NPD Type A </li></ul></ul><ul><ul><ul><li>0-5% ASM activity </li></ul></ul></ul><ul><ul><ul><li>Niemann (Germany) 1914; more severe disease, neurologic involvement; life expectancy is 2 to 3 years </li></ul></ul></ul><ul><ul><li>NPD Type B </li></ul></ul><ul><ul><ul><li>2-10% ASM activity, ASM greater substrate effect; less lysosomal storage </li></ul></ul></ul><ul><ul><ul><li>Pick (Germany) 1927; Less severe, can live into adulthood </li></ul></ul></ul><ul><ul><li>Types C and D NPD — two forms of distinct disease caused by abnormalities in cholesterol-metabolizing gene </li></ul></ul>
  4. 4. Characteristics of NPD Type A Child Neurology © 2000 Menkes, M.D., John H. & Sarnat, M.D., Harvey B.
  5. 5. Genetics of NPD Type A <ul><li>Autosomal Recessive </li></ul><ul><ul><li>The gene for ASM located on human chromosome 11 </li></ul></ul><ul><ul><li>Occurs in Ashkenazi Jews at rate of 1 in 40,000 </li></ul></ul><ul><ul><li>90% of Ashkenazi Jews with Type A NPD have &quot;common&quot; mutations occurring in ASM genes: &quot;L302P,&quot; &quot;fsP330,&quot; and &quot;R496L&quot; </li></ul></ul><ul><ul><li>“ Wildcard” or unique family mutations account for other 10% </li></ul></ul><ul><ul><li>Some patients have both common and wildcard mutations such as the patient at hand </li></ul></ul>
  6. 6. Biochemistry of Sphingomyelin
  7. 7. Therapeutic Approaches <ul><li>Enzyme Replacement Therapy </li></ul><ul><ul><li>NPD A—Doesn’t cross blood-brain barrier; may be used in tandem with gene therapy. </li></ul></ul><ul><ul><li>NPD B—In preclinical studies </li></ul></ul><ul><li>Small Molecule </li></ul><ul><ul><li>Pharmacogenomics—Stop Codon or “nonsense” mutation </li></ul></ul><ul><ul><li>Pharmacological Chaperone —“missense” mutation </li></ul></ul><ul><li>Gene Therapy </li></ul><ul><ul><li>Gene transplantation using viral vectors (Adeno Associated Virus) </li></ul></ul><ul><ul><li>Stem Cell </li></ul></ul>
  8. 8. Case Review <ul><li>35 month female with NPD Type A </li></ul><ul><ul><li>common missense mutation (R496L) </li></ul></ul><ul><ul><li>rare nonsense (stop codon) mutation (R441X) </li></ul></ul><ul><ul><li>Both in ASM gene </li></ul></ul><ul><ul><li>With approval Stanford Ethics Committee </li></ul></ul><ul><ul><li>Intranasal gentamicin used to promote read through of stop codon and production of full length ASM </li></ul></ul><ul><ul><li>Based on report of gentamicin-induced read through of CF stop codon (NEJM 10/9/2003) </li></ul></ul><ul><ul><li>Problem: gentamicin minimally crosses blood brain barrier </li></ul></ul>
  9. 9. Diagnosis of NPD Type A
  10. 10. Mode of Action of Aminoglycosides in Altering Translational Fidelity <ul><li>During bacterial protein synthesis </li></ul><ul><li>Translation initiated with 30S ribosomal subunit binding to mRNA sequence at start codon AUG </li></ul><ul><li>tRNA with complementary anticodon (UAC) </li></ul><ul><li>tRNA carries the aa f-methionine (fMet); forms H-bonds with the AUG start codon </li></ul><ul><li>Forms initiation complex for translation </li></ul>
  11. 11. Mode of Action of Aminoglycosides in Altering Translational Fidelity <ul><li>Next - 50S ribosomal subunit joins complex </li></ul><ul><li>Aminoglycoside antibiotics (e.g. streptomycin, gentamicin) </li></ul><ul><li>Bind to the 30S subunit of bacterial ribosomes </li></ul><ul><li>Block the attachment of the 50S subunit to the initiation complex. </li></ul>
  12. 12. Mammalian Read through <ul><li>Patient’s R441X mutation tetranucleotide sequence (UGAA) is amenable to read through </li></ul><ul><li>UGAA context ranked near the top of 12 tetratnucleotide stop sequences </li></ul><ul><li>Similar rank to CF mutations (UGAG, UAGA) </li></ul>Context 2 UGAC UAGU UGAA UGAG UAGC . . . . . . UAAU Context 1 UGAC UAGU UAGC UGAA UAGA . . . . . . UAAU Most Read- through Least Read- through 1 2 3 4 5 6 7 8 9 10 11 12
  13. 13. Progress to Date with Patient <ul><li>Gentamicin start May 23, 2003 </li></ul><ul><li>Intranasal administration. </li></ul><ul><li>Under 0.1mg/kg through August. </li></ul><ul><li>Ramped up dose to 1.5 mg/kg through September to combat rising cholesterol and triglycerides. </li></ul>808 274 Peak during ramp up (9/16/03) 284 187 Most recent (3/9/04) 383 273 Average of 3 tests prior to Gentamicin treatment (pre 5/23/03) Triglycerides Cholesterol
  14. 14. Oxazolidinone for Read Through of Stop Codons
  15. 15. Oxazolidinone for Read Through of Stop Codons <ul><li>Oxazolidinones - new class of synthetic antibiotics </li></ul><ul><li>Bind to 50 S ribosomal subunit </li></ul><ul><li>Causes translational inaccuracy in vivo: (1) Frameshifting, (2) Read through of stop codons, (3) aa misincorporation </li></ul><ul><li>Linezolid - an oxazolidinone - recently released for resistant gram positive bacterial infections (VRE) </li></ul><ul><li>Safe, used in children, good oral absorption </li></ul>
  16. 16. Linezolid Trial as Stop Codon Read Through Promoter <ul><li>Linezolid preferable to gentamicin </li></ul><ul><ul><li>Better read through of stop codon </li></ul></ul><ul><ul><li>Penetration of blood brain barrier </li></ul></ul><ul><ul><li>Good oral absorption </li></ul></ul><ul><li>Started on 4/6/04 at 5mg/kg every 8 hrs orally </li></ul>
  17. 17. Example of Integrative Medicine: Sophia’s Healing Circle
  18. 18. Example of Integrative Medicine: Sophia’s Healing Circle Allopathic Medicine Traditional Medicine Nutrition Naturopathy Medical Research Physical/ Energy Therapies Spiritual/ Psychological Family & Community Support
  19. 19. Acknowledgements <ul><li>Research Team </li></ul><ul><li>Richard Ellson </li></ul><ul><li>Karen Herzog </li></ul><ul><li>Lucy Hu, O.M.D., LAc </li></ul><ul><li>Sylvestre Quevedo, M.D . </li></ul><ul><li>Richard Sachs </li></ul><ul><li>Other Contributors </li></ul><ul><li>Greg Enns, M.D. </li></ul><ul><li>Richard Moss, M.D. </li></ul><ul><li>Lucile Packard Children’s Hospital at Stanford Ethics Committee </li></ul><ul><li>Ed Schuchman, PhD. </li></ul><ul><li>Greg Stewart, PhD. </li></ul>
  20. 20. For More Information <ul><li>Center for Integrative Medicine (CIM) </li></ul><ul><li> </li></ul><ul><li>International Center for Types A and B Niemann-Pick Disease </li></ul><ul><li> </li></ul><ul><li>Osher Center for Integrative Medicine </li></ul><ul><li>University of California School of Medicine </li></ul><ul><li> </li></ul><ul><li>Sophia’s Garden Foundation </li></ul><ul><li> </li></ul>