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Volume 08
Clinical Pharmacology & Biopharmaceutics
ISSN: 2167-065X
Pharmacology 2019
World Heart Congress 2019
August 19-20, 2019
JOINT EVENT
conferenceseries
.com
August 19-20, 2019 Vienna, Austria
&
7
th
World Heart Congress
24
th
World Congress on
Pharmacology
The project of experimental testing of the hypothesis regarding the effect of sodium phenylbutyrate for
reducing dopamine depletion in the brain in Lesch-Nyhan syndrome using new personalized genetic
HPRT1-deficient mouse as a pharmacological model
Maria I. Yablonskay
1
, Vladislav A. Kalmykov
2
, Yuliya Yu. Silaeva
2
, Victoria Yu. Voinova
1
and
Alexey V. Deykin
2
1
Russian National Research Medical University, Russian Federation
2
Institute of Gene Biology of the Russian Academy of Sciences, Russian Federation
L
esch-Nyhan syndrome is an X-linked inborn error of purine metabolism which is caused by mutations in the
HPRT1 gene encoding the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPTR),
the prevalence is approximately 1:380000. The disease manifests during the first year of life and is characterized by
uric acid overproduction and urate nephropathy combined with severe neurologic dysfunction including cognitive
impairment, dystonia, choreoathetosis, spasticity and self-injurious behavior. Overproduction of uric acid is
controlled well with allopurinol. But until now, there is no sufficiently effective pharmacologic therapy for neurologic
dysfunction in Lesch-Nyhan syndrome. We hypothesized that HPRT deficiency leads to hyperactivation of guanine
deaminase (GDA), which has the same localization and expression levels in the brain as HPRT. GDA irreversibly
converts guanine to xanthine with the release of ammonia. Local excess of ammonia in brain structures triggers
a cascade of pathological processes resulting in impaired transport and release of dopamine in the nigrostriatal
pathway, hyperactivation of the NMDA receptors and combined hyperactivation of adenosine and dopamine
receptors, neuronal insensitivity to exogenous dopamine. We offer to test the effect of ammonia binding remedy
Sodium Phenylbutyrate for reducing dopamine depletion in the brain. To test this hypothesis, we created a new
personalized genetic HPRT1-deficient mouse model. We used the CRISPR-Cas9 genomic editing system to introduce
the deletion of 8Val in the first exon of the HPRT1 gene in the mouse model. This hemizygous mutation is the cause
of Lesch-Nyhan syndrome in one of the patients observed in our clinic. Despite the fact that Hprt-deficient mice do
not demonstrate a clinical complex characteristic of patients with Lesch-Nyhan syndrome, they have depletion of
dopamine in the same brain structures. These models should be used in studies of brain metabolism and preclinical
studies of the effectiveness of new treatments for this disease.
Recent Publications :
1. Fu R., Jinnah H.A. (2011) Genotype-phenotype correlations in Lesch-Nyhan disease: moving beyond the gene.
Journal of Biological Chemistry 287(5): 2997–3008.
2. Torres R.J., Puig J.G. (2007) Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-
Nyhan syndrome. Orphanet Journal of Rare Disseases 2: 48.
3. Fairbanks L.D., Jacomelli G., Micheli V., Slade T., Simmonds H.A. (2002) Severe pyridine nucleotide depletion
in fibroblasts from Lesch-Nyhan patients. Biochemical Journal 366(Pt 1): 265–272.
4. Deutsch S.I., LongK.D.B., RosseR.B.,Mastropaolo J., Eller J. (2005)Hypothesizeddeficiency of guanine-based
purines may contribute to abnormalities of neurodevelopment, neuromodulation and neurotransmission in
Lesch-Nyhan syndrome. Clinical Neuropharmacology 28: 28–37.
5. Meek S., Thomson A.J., Sutherland L., Sharp M.G., Thomson J., Bishop V., et al. (2016) Reduced levels of
dopamine and altered metabolism in brains of HPRT knock- out rats: a new rodent model of Lesch-Nyhan
Disease. Scientific Reports 6: 25592.
Maria I. Yablonskaya et al., Clin Pharmacol Biopharm, Volume 08