Header Logo

Search Result Details

This page shows the details of why an item matched the keywords from your search.
One or more keywords matched the following properties of Ginns, Edward
PropertyValue
overview

Our research is directed toward identifying, understanding and reversing the consequences of gene mutations on protein and cell function in inherited human disease. Cell biological and molecular genetic approaches are used in conjunction with clinical studies to obtain a better understanding of gene expression and the molecular pathophysiology underlying selected Mendelian and complex trait diseases. To accomplish this objective, we study gene variation and function in unique human genetic isolates, inbred animal models and families with inherited developmental disorders. Research projects reflect a “bench to bedside” approach, combining efforts from interdisciplinary investigations on humans and animal models. Current study areas include the link between Gaucher disease and parkinsonism, development of novel gene and replacement therapies for Gaucher disease, and the genetics of selected psychiatric disorders, including bipolar affective disorder in the Old Order Amish and obsessive compulsive disorder in domestic animals. 

Gaucher Disease Therapy

This research area focusus on the development of new oral biologics for treating Gaucher Disease. Gaucher Disease a lysosomal storage disorder caused by inherited deficiencies of the enzyme glucocerebrosidase (GBA). Decreases in functioning GBA levels lead to lipid accumulation in the spleen, liver, brain and bone marrow that cause a wide range of clinical manifestations. There are 3 different types of this disease based on the presence or absence of early onset brain involvement. Type 1 is the most common form of Gaucher disease with no neuropathic phenotypes and accounts for more than 90% of all cases. Type 2 is rare and involves severe neurological (brain stem) abnormalities. It is usually fatal within the first 2 years, and it is currently untreatable because of the severe, irreversible brain damage. Type 3 shows similar symptoms as type 1 as well as neurological involvement.

Currently, available treatments for Gaucher disease include enzyme replacement (ERT) and substrate reduction therapies. ERT involves receiving intravenous (IV) infusions about every 2 weeks and can cost up to $200,000 or more each year.

This research will use orally administered glucan particles containing DNA to produce increased levels of functioning GBA. Success of the treatments will be determined by following GBA levels and biomarkers in various tissues of the mice during treatment. An increase in GBA should also lead to a decrease in the lipid glucocerebroside (GL1) and glucosylsphingosine (lyso-GL1).

Gaucher Disease Linked Parkinsons

We are using mouse models of Gaucher disesase to (i) identify novel molecular abnormalities impacting pathophysiology of  Gaucher related PD and sporadic PD, (ii) carry out longitudinal studies of PD progression and biomarker discovery, and (iii) enable testing of novel strategies for treatment, intervention, and potentially even prevention of Gaucher disease and Parkinsons.

Recent clinical, epidemiological and experimental studies have confirmed a strong connection between Parkinson’s disease (PD) and individuals carrying a glucocerebrosidase gene (GBA) Gaucher mutation.  We are building upon our published in-vivo findings of altered nigrostriatal pathway dopaminergic neurotransmission in the conduritol-beta-epoxide (CBE) pharmacological Gaucher mouse model of reduced GBA enzyme activity.  This is the first description in an animal model to recapitulate the synaptic dysfunction reported in human striatal imaging studies of Gaucher mutation carriers asymptomatic for Parkinsonism.  CBE administration produced markedly reduced evoked dopamine release and post-synaptic density size.  These synaptic abnormalities were accompanied by robust elevation of neuroinflammatory markers and alpha-synuclein (a-syn) in nigrostriatal tissue.  To further address the unmet need for better understanding and treatment of bone and brain involvement in Gaucher disease, and more specifically as models for the study of Gaucher-related Parkinsonism and sporadic Parkinson’s disease, we are using two long-lived transgenic mouse models of Gaucher disease bearing the L444P or the R463C point mutations frequently found in Gaucher patients.  These aged homozygous Gaucher transgenic mutant mice have a lifespan of from 1-2 years and show abnormal a-syn accumulation and astroglial activation in the striatum.

 

Search Criteria
  • Dopamine