Lysosomal storage disorders (LSDs)
Several genetic diseases are caused by a deficiency in lysosomal enzymes. These enzymes normally function to degrade different types of molecules. When these enzymes are missing or reduced in activity, their substrates accumulate in lysosomes and lead to disease. A subset of these lysosomal storage disorders (LSDs) are cause defects in the enzymes that degrade glycolipids including Gaucher disease, Fabry disease, and GM2 and GM1 gangliosidosis. Other genetic disease involving glycolipids
The dysregulation of glycolipid metabolism plays roles in other genetic diseases besides the lysosomal disorders. For examples, in polycystic kidney disease (PKD), the elevation of glycosphingolipids (GSLs) contributes to inflammatory and proliferative processes that drive cyst growth and progression to end stage kidney disease. Glycosphingolipids have also been implicated in a subset of Parkinson’s Disease patients that are carriers of mutations in GBA (GBA-PD). In these individuals accumulated glycolipids are thought to promote the aggregation and production of pathogenic forms of the protein alpha-synuclein.
More than 60 genetic diseases are currently known to directly or indirectly affect kidney function. These diseases range from relatively common to very rare and can impact kidney functions in infants to adults. Many of these diseases are progressive and eventually lead to chronic kidney disease (CKD) and eventually end stage renal disease (ESRD). Unfortunately, for the majority there are no disease modifying therapeutic options and patients eventually resort to renal replacement therapies (RRT) including chronic dialysis or transplant. With their high prevalence and limited therapeutic options, these kidney diseases present a significant health care and economic challenge.
While our initial focus is on developing therapies for genetic diseases associate with GSL metabolism, AceLink’s goal is to diversify the pipeline by developing therapies that address the unmet clinical need for a broader set of kidney diseases such as diabetic nephropathy, IgA nephropathy, or kidney stone related kidney damage.
Gaucher disease is a lysosomal storage disorder caused by a mutation in the GBA1 gene. Mutation in GBA1 lead to reduced activity of the lysosomal enzyme glucocerebrosidase (GCase). In Gaucher patients, GCAse deficiency results in the accumulation of glucosylceramide (GL1). Depending on the severity of the GCase deficiency, Gaucher patients can develop neurological symptoms as is seen in type II and III Gaucher disease or they can develop milder non-neurological symptoms as are seen in type I Gaucher disease.
Enzyme replacement therapy (ERT) and small molecule substrate reduction therapies (SRT) are available for Gaucher disease, but these therapies do not address the neurological features of Gaucher disease because they do not cross the blood brain barrier. AceLink is developing brain penetrant small molecule SRT that could be used to treat both CNS and non-CNS symptoms of Gaucher disease.
Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene, leading to reduced activity of the enzyme a-galactosidase A (GalA). In Fabry disease patients, GalA deficiency results in the accumulation of globotriaosylceramide (GL3), leading to a wide range of symptoms from pain, gastrointestinal issues, eye and skin problems to kidney failure, heart disease, and stroke. Fabry disease is an x-linked disorder and it more commonly seen in males although females can also develop Fabry disease that is usually milder. It is estimated that 1 in 50,000 males are affected by Fabry disease.
Enzyme replacement therapy (ERT) is the standard of care for Fabry disease. While ERT reduces progression of many Fabry symptoms, the benefits are incomplete due to the low penetration of enzyme into some cell types. Many patients on ERT still develop progressing kidney and heart disease. There are other shortcomings of ERT, such as high cost, burden of life-long intravenous infusion, and allergic reaction to ERT. The limitations of ERT highlight the need for safe and effective small molecule therapies that are more efficient at penetrating diverse cell types and tissues.
AceLink is developing a GCS inhibitor AL01211 to treat Fabry disease.
GM1 Gangliosidosis is a lysosomal storage disorder caused by a mutation in the GLB1 gene. Mutation in GLB1 lead to reduced activity of the lysosomal enzyme beta-galactosidase (bGal). In GM1 gangliosidosis patients, bGal deficiency results in the accumulation of GM1 gangliosides (GM1). GM1 gangliosidosis patients with the most severe bGal deficiency develop severe early onset neurological symptoms while milder bGal deficiency can lead to later onset neurological symptoms.
GM2 ganglisosidosis is a group of lysosomal storage disorders caused by mutations in the HEXA or HEXB genes. Tay-Sachs disease is a form of GM2 gangliosidosis caused by mutations in the HEXA gene and Sandhoff disease is caused by mutations in the HEXB gene. Together HEXA and HEXB encode protein subunits of the beta-hexosaminidase enzyme. Mutation in HEXA or HEXB lead to reduced activity of the lysosomal enzyme beta-hexosaminidase enzyme (bHex). In GM2 gangliosidosis patients, bHex deficiency results in the accumulation of GM2 gangliosides (GM2). GM2 gangliosidosis patients with the most severe bHex deficiency develop severe early onset neurological symptoms while milder bGal deficiency can lead to later neurological symptoms.
AceLink is developing brain penetrant small molecule SRT that could be used to treat GM1 and GM2 gangliosidosis.
POLYCYSTIC KIDNEY DISEASE
Polycystic kidney disease (PKD) is a genetic disorder in numerous cysts develop primarily within the kidneys, causing the kidneys to enlarge and eventually lose function. There are two main subtypes of PKD:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, characterized by the development of numerous fluid-filled cysts, kidney enlargement, and eventual progression to chronic kidney disease (CKD) and end-stage renal disease (ESRD). While some severe forms of ADPKD can affect young children, most PKD patients develop symptoms in early adulthood or later. The probability of progressing to ESRD increases with age, with 50% of ADPKD patients over the age of 60 years requiring dialysis or kidney transplantation. The majority of ADPKD cases are caused by a mutation in one of two genes, PKD1 or PKD2. These two proteins localize to the primary cilia of renal epithelial cells and play an important role in regulating renal development and function, promoting epithelial differentiation, and preventing cell proliferation.
Autosomal recessive polycystic kidney disease (ARPKD) is also characterized by the formation of kidney cysts and enlargement leading to ESRD. In contrast to the dominant disease, ARPKD is typically a more severe and earlier onset disease that usually develops in utero or early childhood. Most cases of ARPKD arise from mutations in the PKHD1 gene, which encodes the fibrocystin protein. Fibrocystin also localizes to the primary cilia of renal epithelial cells where it is required for renal development and maintenance. Fibrocystin has been shown to associate with the polycystin complex (PC1-PC2) and its deficiency impact similar proliferative pathways to promote cyst formation, kidney enlargement, and progression to ESRD.
The glycosphingolipids GL1 and GM3 are elevated in kidney tissue from patients with poly cystic kidney disease and in animal models of polycystic kidney disease. Studies using GCS inhibitors in multiple different animal models of PKD have demonstrated that reducing the production of GSLs can slow cyst growth and preserve kidney function.
GBA PARKINSONS' DISEASE
GBA Parkinson’s disease is arguably the most common genetic form of Parkinson’s disease. Numerous genetic studies have shown that a single mutation in the GBA1 gene (the gene that causes Gaucher disease) can increase your risk of developing Parkinsons’ disease by up to 30-fold. In vitro and in vivo preclinical studies suggest that the protein alpha-synuclein can interact with glycolipids and this can lead to aggregation and toxicity. Studies using GCS inhibitors in mouse models of Parkinson’s disease support that lowering the production of these glycolipids using can reduce synuclein aggregation, slow the progression of neurobehavioral phenotypes, and neurodegeneration.
DIABETIC NEPHROPATHY (DN)
Diabetic nephropathy (DN) is a common form of kidney damage that occurs with the progression of metabolic diseases like type I and type II diabetes. If diabetes is not properly treated then damage can occur to the glomeruli, the filtration units of the kidney. This damage can lead to high blood pressure, which puts more pressure on the remaining healthy kidney and leads to more damage, chronic kidney disease, (CKD) and eventual progression to end stage kidney disease (ESRD).
Glycolipids have been shown to play roles in metabolic disease. Elevated levels of glycolipids contribute to insulin resistance and lowering glycolipdis with GCS inhibitors can increase insulin sensitivity and improve glucose tolerance. Glycolipids are elevated in the kidneys of diabetic nephropathy patients where they likely contribute to inflammation, hypertrophy, and fibrosis. Therefore, treating patients with GCS inhibitors have the potential to target both the metabolic disease and the resulting tissue damage occurring in DN.