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

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

Incidences of LSD

Background of NPD
Types A and B NPD — two forms of same disease caused by mutations in gene for acid sphingomyelinase (ASM)
Results in reduced ASM activity in cellular lysosomes leading to sphingomyelin storage (lysosomal storage)
NPD Type A
0-5% ASM activity
Niemann (Germany) 1914; more severe disease, neurologic involvement; life expectancy is 2 to 3 years
NPD Type B
2-10% ASM activity, ASM greater substrate effect; less lysosomal storage
Pick (Germany) 1927; Less severe, can live into adulthood
Types C and D NPD — two forms of distinct disease caused by abnormalities in cholesterol-metabolizing gene

Genetics of NPD Type A
Autosomal Recessive
The gene for ASM located on human chromosome 11
Occurs in Ashkenazi Jews at rate of 1 in 40,000
90% of Ashkenazi Jews with Type A NPD have "common" mutations occurring in ASM genes: "L302P," "fsP330," and "R496L"
“ Wildcard” or unique family mutations account for other 10%
Some patients have both common and wildcard mutations such as the patient at hand

Biochemistry of Sphingomyelin

Therapeutic Approaches
Enzyme Replacement Therapy
NPD A—Doesn’t cross blood-brain barrier; may be used in tandem with gene therapy.
NPD B—In preclinical studies
Small Molecule
Pharmacogenomics—Stop Codon or “nonsense” mutation
Pharmacological Chaperone —“missense” mutation
Gene Therapy
Gene transplantation using viral vectors (Adeno Associated Virus)
Stem Cell

Case Review
35 month female with NPD Type A
common missense mutation (R496L)
rare nonsense (stop codon) mutation (R441X)
Both in ASM gene
With approval Stanford Ethics Committee
Intranasal gentamicin used to promote read through of stop codon and production of full length ASM
Based on report of gentamicin-induced read through of CF stop codon (NEJM 10/9/2003)
Problem: gentamicin minimally crosses blood brain barrier

Diagnosis of NPD Type A

Mode of Action of Aminoglycosides in Altering Translational Fidelity
During bacterial protein synthesis
Translation initiated with 30S ribosomal subunit binding to mRNA sequence at start codon AUG
tRNA with complementary anticodon (UAC)
tRNA carries the aa f-methionine (fMet); forms H-bonds with the AUG start codon
Forms initiation complex for translation

Mode of Action of Aminoglycosides in Altering Translational Fidelity
Next - 50S ribosomal subunit joins complex
Aminoglycoside antibiotics (e.g. streptomycin, gentamicin)
Bind to the 30S subunit of bacterial ribosomes
Block the attachment of the 50S subunit to the initiation complex.

Mammalian Read through
Patient’s R441X mutation tetranucleotide sequence (UGAA) is amenable to read through
UGAA context ranked near the top of 12 tetratnucleotide stop sequences
Similar rank to CF mutations (UGAG, UAGA)
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

Progress to Date with Patient
Gentamicin start May 23, 2003
Intranasal administration.
Under 0.1mg/kg through August.
Ramped up dose to 1.5 mg/kg through September to combat rising cholesterol and triglycerides.
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

Oxazolidinone for Read Through of Stop Codons

Oxazolidinone for Read Through of Stop Codons
Oxazolidinones - new class of synthetic antibiotics
Bind to 50 S ribosomal subunit
Causes translational inaccuracy in vivo: (1) Frameshifting, (2) Read through of stop codons, (3) aa misincorporation
Linezolid - an oxazolidinone - recently released for resistant gram positive bacterial infections (VRE)
Safe, used in children, good oral absorption

Linezolid Trial as Stop Codon Read Through Promoter
Linezolid preferable to gentamicin
Better read through of stop codon
Penetration of blood brain barrier
Good oral absorption
Started on 4/6/04 at 5mg/kg every 8 hrs orally

Example of Integrative Medicine: Sophia’s Healing Circle

Example of Integrative Medicine: Sophia’s Healing Circle Allopathic Medicine Traditional Medicine Nutrition Naturopathy Medical Research Physical/ Energy Therapies Spiritual/ Psychological Family & Community Support

Acknowledgements
Research Team
Richard Ellson
Karen Herzog
Lucy Hu, O.M.D., LAc
Sylvestre Quevedo, M.D .
Richard Sachs
Other Contributors
Greg Enns, M.D.
Richard Moss, M.D.
Lucile Packard Children’s Hospital at Stanford Ethics Committee
Ed Schuchman, PhD.
Greg Stewart, PhD.

For More Information
Center for Integrative Medicine (CIM)
www.cimsj.com
International Center for Types A and B Niemann-Pick Disease
www.mssm.edu/niemann-pick
Osher Center for Integrative Medicine
University of California School of Medicine
www.ucsf.edu/ocim
Sophia’s Garden Foundation
www.sophiasgarden.org

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

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