3/17/16

1

Sandeep Kumar & Robert C. Pena

(March 16, 2016)

�� Hexosaminidase Enzyme (αβ heterodimer) and Cofactor GM2 Activator (GM2A) complex to

hydrolyze GM2 ganglioside lipids in neural tissue (NHGRI, 2011)� Mutations cause accumulation of lipids and fatty tis sue in brain and nervous systems , leading to deterioration of neural

tis sue integrity, interruption of function, and fatal damage

� Ganglioside functions and locations (Nelson & Cox, 2005; Stryer, 1975)� Fund mostly in the nervous sys tem and make up 6% of all phospholipids � Used for cell-cell recognition/communication at surface level� Crucial in neural growth/differentiation and as carcinogenes is marker

� Mutations and associated diseases (Boles & Proia, 1995; Proia & Sarovia, 1987) � Hex-A (α subunit) recess ive mutation → Tay-Sachs Disease� Hex B (β subunit) mutation → Sandhoff Disease� GM2A → GM2 Ganglios idos is (clinically identical to TSD and SD)� Mutations in all 3 cases are recess ive (Hex Gene found on C. 15)� 80% of all infant-onset TSD caused by 4bp insertion (TATC) into exon 11 of HexA gene

� Population Prevalence (NHGRI, 2011)� Carrier parents each have 50% of pass ing to children � Higher prevalence in Ashkenazi (Eas tern European) Jewish populations (1/27 = 3.7% of all AJs in US are carriers )

Genetic and Physiological Causes of TSD

�� Early Fetal Stages

� Destruction and interruption of normal neural tis sue development and activity begin

� 0-6 Months of Age� Normal phys ical presentation

� Post-6 Months of Age� Clear onset of neurological damage� Slowed development

� 0.5-2 Years of Age� Recurrent seizures� Subs tantially reduced mental functionality� Regress ion of infant(loss of ability to crawl, s it up, turn over)

� 2-4 Years of Age� Blindness� Paralys is , limited or no response to external s timuli

� 5 Years of Age� TSD is typically fatal at this point

Source: National Human Genomic Research Institute

Timeline of Symptom Presentation�

� No curative treatment yet exists for TSD, so all care is palliative (treats symptoms/slows deterioration) (Mayo Clinic, 2016)� Anti-epileptics (AEDs) for seizures� Respiratory medication for breathing� Feeding/Gavage Tubes� OT/PT for developmental issues

� Drugs, chemical therapeutics, and vector-based gene therapies cannot effectively reach diseased cells because of blood-brain barrier (Guyton & Hall, 2005)� N-butyldeoxynojirimycin to prevent lysosomal storage of lipids (Platt et al. 1997)� Engraftment of transduced progenitor/stem cells (Lacorazza et al., 1996)

� Continuing development of genetic therapies to correct for mutated gene using retro/adeno/lentiviral vectors, CRISPR/Cas9, Zinc Finger Nucleases (ZFNs), TALEN (Cosgrove, 2016)� Success with adenoviruses causing overexpression of both functional subunits in mouse

livers (Guidotti et al., 1999)

Possible Treatments for TSD

3/17/16

2

�1. Anon. (2011). “Learning About Tay-Sachs Disease”. National Human Genome Research Ins titute. Retrieved 12

March 2016 from http://www.genome.gov/100012202. Anon. (2016). “Tay-Sachs Disease”. Mayo Clinic. Retrieved 12 March 2016 from http://tinyurl.com/mjelzw43. Boles , D. & Proia, R. (1995). The molecular bas is of HEXA mRNA deficiency caused by the mos t common Tay-

Sachs disease mutation. American Journal of Human Genetics, 56: 716-7244. Cosgrove, B. (2016). BME 6110: Stem Cell Engineer ing. Lectures conducted from Cornell Univers ity, Ithaca, NY5. Guidotti, J . et al. (1999). Adenoviral gene therapy of Tay-Sachs disease in hexosaminidase A-deficient knockout

mice. Human Molecular Genetics , 8(5): 831-838. doi: 10.1093/hmg/8.5.8316. Guyton, A. & Hall, J . (2011). Guyton and Hall Textbook of Medical Phys iology. (12th ed.). Philadelphia, PA:

Saunders7. Lacorazza, H. et al. (1996). Express ion of human β–hexosaminidase α–subunit gene (the gene defect of Tay–

Sachsdisease) in mouse brains upon engraftment of transduced progenitor cells . Nature Medicine, 2: 424-429. doi: 10.1038/nm0496-424

8. Nelson, D. & Cox, M. (2005). "Lipids". Lehninger Pr inciples of Biochemis try, 4th edition. W.H. Freeman & Co., p. 357. ISBN: 9780716743392

9. Platt, F. et al. (1997). Prevention of lysosomal s torage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science, 276 (5311): 428-431: doi: 10.1126/science.276.5311.428

10. Proia, R. & Soravia, E. (1987). Organization of the gene encoding the human beta-hexosaminidase alpha-chain. J. Biol. Chem, 262(12): 5677–81. PMID: 2952641

11. Stryer, L. (1975). Biosynthes is of Macromolecular Precursors . Biochemsitry. W.H. Freeman & Co., p. 486. ISBN: 0-7167-0174-X

References