Our Priorities
We focus in areas where our technologies can provide the most benefit for patients. This means diseases involving loss of function mutations or haploinsufficiency. Our current therapeutics portfolio is below.
Progranulin:
Central Player in Neuroinflammation, and Cause of Familial Frontotemporal Dementia
Mutations in the Progranulin gene cause familial frontotemporal dementia (fFTD) by deleting one of the two functioning copies of the gene and reducing progranulin levels in the brain (a situation known as haploinsufficiency). Frontotemporal dementia results from the degeneration of neurons in the frontal lobe, the portion of the brain responsible for personality, language and behavior. The majority of cases effect people between the ages of 45 and 64, and it is the most common dementia in people under 60. The FTD Association has an excellent review of FTD at their website.
Progranulin is a key player in keeping the brain’s innate immune cells in balance, and when patients have half as much progranulin as they should (when they’re haploinsufficient) there is not enough progranulin to protect their neurons, and degeneration occurs in a process called neuroinflammation.
Using the CoreX and AlloChem platforms, Sharp has discovered a series of compounds that protects progranulin from degradation in the brain, allowing levels of progranulin to increase almost two-fold, back to normal levels in healthy individuals (figure below).
We are pursuing these compounds as orally available therapies that will treat the underlying imbalance in fFTD, with a chance to stop the disease in its tracks, and potentially reverse some of the atrophy leading to improved function. Eventually these therapies could be used as a preventative for family members who have the progranulin mutation, but have not yet started showing symptoms.
Impact Far Beyond fFTD
As important as an effective treatment for the familial subset of FTD would be for families living with this disease, these patients have taught us that progranulin’s biology is far-reaching. Progranulin-elevating therapies like those we’re developing could have significant impact for other neurodegenerative disorders. That’s because of progranulin’s role in reducing neuroinflammation, the imbalance behind many neurodegenerative diseases.
Cells called glia surveil the brain to make sure that there is no bacterial or other infection. When glia encounter the remnants of a bacterial cell wall, they become highly activated, calling other immune cells to the site. These cells work together to clear the infection, and things return to normal. The glia become deactivated, moving into a repair and healing phase. Unfortunately, other molecules in the brain can stimulate glial cells, causing them to activate. Most notable are the protein aggregates that are the hallmark of most neurodegenerative diseases, and that accumulate in the brain as we age. These are called the proteinopathy diseases of the CNS, see this recent review for more information, especially Figures 1 and 2.
When glia become activated by protein aggregates they secrete factors that put stress on neurons and can kill them outright. The problem is that unlike a bacterial infection, the brain can’t clear the protein aggregates, and the inflammation goes on continuously until neurons die and dementia results.
Progranulin plays a key role in preventing this activation, moving glia back to a repair and healing behavior (where aggregates can be cleared). We believe that increasing levels of progranulin in the brain will help patients who have two normal copies of progranulin, but that have elevated levels of aggregated proteins and neuroinflammation. That includes patients with:
FTD - all forms
Alzheimer’s Disease
Parkinson’s Disease
ALS
Huntington’s
Progressive MS
Traumatic Brain Injury
We are pursuing all of these indications to bring this critical biology to the benefit of patients.
GBA
Cause of Gaucher’s Disease, Major Risk Factor in Parkinson’s
The GBA gene codes for an enzyme Glucosylceramidase (which we’ll also call GBA) an enzyme involved in making key lipid components of the cell wall. Mutation of this enzyme results in the inability to properly make these lipids and gives rise to Gaucher’s disease. Gaucher’s is a classic “substrate accumulation disease”. Without the GBA protein, the substrates build up, and cells are deprived of the products of the enzyme. In Gaucher’s it is substrate buildup that leads to disease.
In Gaucher’s both copies of the GBA gene are mutated; this is an autosomal recessive disease. If you have one normal copy of GBA, and one mutated copy you are a Gaucher’s carrier and don’t get Gaucher’s (we’ll come back to Gaucher’s carriers in a moment). An effective therapy for Gaucher’s would restore function of the mutated protein in order to provide enough enzymatic activity to begin converting substrate to product, relieving substrate accumulation. This has been done quite effectively by infusing patients with the normal form of the enzyme manufactured in a biotechnology protein production facility in work pioneered at Genzyme. The infused enzyme takes the place of the mutated enzyme and begins converting substrate into product, reversing the course of the disease.
Sharp we are developing small molecule therapeutics that have the same effect. Using our CoreX assays and AlloChem libraries we have discovered the SEL_148,721 series of compounds that can substantially restore GBA activity in cells from patients. This is an excellent example of “Patient Driven Science” as there is no better model of the mutated protein having lower enzyme activity than in Gaucher’s patients themselves.
With the ‘721 series compounds we are able to restore GBA activity to normal levels in Type I Gaucher’s patient cells.
Gaucher’s Carriers Have Increased Risk of Parkinson’s
In much the same way as familial FTD patients taught us the important role progranulin plays in neurodegeneration, Gaucher’s patients have taught us the important role of GBA activity in Parkinson’s (again, Patient-Driven Science). Prior to Genymze releasing Ceredase (and eventually Cerezyme) very few Gaucher’s patients lived long enough to get Parkinson’s disease. However, with this highly effective therapy, patients were now living longer, long enough to get Parkinson’s, which they did at 20-times the normal rate. Because the Genzyme therapy did not get into the brain it could not treat the CNS component of Gaucher’s.
Interestingly when genetic studies were done in Parkinson’s patients it was determined that mutation of a single copy of GBA (in other words, being a Gaucher’s carrier) increased the risk of Parkinson’s by 8-10 fold.
This has been a recurring theme. There are no unnecessary proteins, evolution would select against that. So, when a gene is mutated some critical function is lost, and we learn important information about what this protein is doing, and why it’s necessary. Armed with that information we can frequently find other conditions that relate to the loss of this same protein; perhaps in carriers like above for GBA or manifestations in other organs for people with less severe mutations.
The relationship between GBA and Parkinson’s is similar to the relationship between progranulin and fFTD. GBA/Parkinson’s patients are haploinsufficient for GBA (they have one functioning and one non-functioning copy of the gene). In this case the goal is the same as in progranulin, activate the remaining normal copy to get a two-fold increase in GBA activity. In addition to activating the mutant GBA for Gaucher’s, Sharp’s compounds also activate the normal copy of the gene. We have seen increases in activity approaching 2-fold, the amount required to reverse the deficit in the Gaucher’s carriers (see Figure).
We are pursuing these compounds for their application in GBA Parkinson’s patients, as well as to provide a convenient orally dosed therapy for Gaucher’s
We’re moving each of these programs towards its next development stage to bring several programs into clinical trials and to patients. Some programs we’ll move forward ourselves, for others we will partner with companies that are better positioned to provide the most benefit to patients.