Elwin Chappell posted an update 4 months ago
The novel epitopes could provide a protective effect and thus lower viral levels, delaying the progression of HIV infection to AIDS. Even though only two overlapping potential epitopes are presented here, it is believed to be significant in supporting an argument that HLA allotype should be taken into consideration when patients start HIV treatment. Gaucher Disease results from a deficiency of the lysosomal enzyme glucocerebrosidase. In the most common phenotype of Gaucher disease, pathology is limited to the reticuloendothelial and S 25585 skeletal systems and there are no neuropathic symptoms. In neuropathic Gaucher disease, subdivided into type 2 and type 3 Gaucher disease, the deficiency of glucocerebrosidase causes glucosylceramide and glucosylsphingosine to accumulate in the brain, leading to neurologic impairment. Type 2 Gaucher disease is characterized by early onset, rapid progression, extensive pathology in the viscera and central nervous system, and death usually by 2 years of age. Type 3 Gaucher disease, also known as subacute nGD, is an intermediate phenotype with varying age of onset and different degrees of severity and rates of progression. A recent development has produced the K14 lnl/lnl mouse model of type 2 Gaucher disease ; this mouse model closely recapitulates the human disease, showing ataxia, seizures, spasticity and a median lifespan of only 14 days.. As in patients with nGD, several mouse models of the disease have increased levels of GluCer and GluSph in the brain due to the deficiency in GC activity. A homozygous GC knockout mouse presents with an,100-fold elevation of GluSph in the brain as early as day 13 of gestation, and these levels increase until early neonatal death from disruption of the epithelial barrier of the skin. An increase in GluSph has also been observed in human fetuses with type 2 Gaucher disease, thus confirming the similarity of the pathologic processes in mice and humans. Restricting GC expression to the skin with a keratin-14 promoter helped overcome the early mortality observed in previous mouse models of the disease. The resulting ‘‘K14’’ mice display a neuropathic phenotype that shares many pathologic features with type 2 Gaucher disease, such as neurodegeneration, astrogliosis, microglial proliferation, and increased levels of GluCer and GluSph in specific brain regions. Clinical management of patients affected by nGD poses a challenge for treating physicians both because of the severity of type 2 disease and the inability of the current therapies to cross the blood brain barrier. In type 3 Gaucher disease, treatment using high doses of intravenous recombinant human glucocerebrosidase has been evaluated. Even though this treatment is useful for reducing visceral disease, it has not provided convincing evidence of its ability to reduce the rate of progression of the neurological symptoms. Recent studies have explored the possibility of directly administering lysosomal enzymes to the brain to circumvent the BBB, and have shown efficient biodistribution, clearance of substrate, amelioration of pathology and behavioral improvements in mouse models of Neuronal Ceroid Lipofuscinosis, Niemann-Pick disease and Gaucher disease. Indeed, we have shown recently that brain pathology and survival in the K14 Gaucher mouse model could be enhanced by intracerebroventricular injection of GC in neonatal animals. Miglustat, a marketed, non specific glucosylceramide synthase inhibitor which crosses the BBB does not appear to address the neuropathic symptoms of nGD. To this point, we have shown in a mouse model of Sandhoff disease that NB-DNJ counterintuitively increases brain GluCer levels, while GZ 112638 a specific GSI in clinical trials, which does not cross the BBB, has no effect as expected. To identify a glucocerebroside synthase inhibitor with the ability to cross the BBB, we screened a series of novel synthetic compounds, resulting in the nomination of GZ 161 as a potential therapeutic. An evaluation of GZ 161 in the K14 mouse model of type 2 Gaucher disease demonstrated that it could indeed reduce brain GluCer and GluSph. It also reduced brain neuropathology and extended the lifespan of this model. Although this substrate reduction approach may have promise for type 3 Gaucher disease, in the K14 model inhibiting GCS in this way did not appear to be as efficacious as supplying GC directly to the murine brain. Thus a combined approach using both enzyme replacement and small molecule substrate reduction may, at least in principle, represent a more effective approach for neuropathic Gaucher disease. wild type mice at 10 days of age, the K14 mouse brain has increased numbers of CD68+ cells in multiple locations. The greatest concentration of CD68+ cells was seen in the thalamus and brainstem, two sites that also show pathology in type 2 Gaucher patients.