Update on the Genetic Research at the University of Massachusetts
By Robert H. Brown, Jr., D.Phil., M.D.
The UMass Team has made progress in three activities in the laboratory. First, we have continued work on our program to find ways to turn off the gene that makes the mutant HSAN protein (serine palmitoyltransferase or SPT). This has involved developing a set of reagents that can interact with the working template of the gene, which is a string of RNA molecules copied from the DNA in the gene itself. Guided by Dr. Anastasia Khvorova and aided by a graduate student, Havisha Karnam, we have made starting tools – short strings of DNA molecules (known as oligonucleotides, or just “oligos”) that bind to the target RNA from the SPT gene. We have generated two types of the oligos and are very encouraged because they both successfully turn off the SPT gene in cells in a Petri dish.
In our second, parallel effort, we have also been studying the degree to which these oligos permeate the target sites in the nervous system (the dorsal root ganglia and spinal cord). We have addressed this in mice, using infusions into the spinal fluid. One of the oligos shows excellent penetration into the target tissues. This provides considerable encouragement that we should be able to take oligo’s that silence SPT in a Petri dish, infuse them into the spinal fluid, and attain good silencing of the SPT gene in the nervous system tissues in the mouse.
In our third line of studies, we have continued the efforts to generate new mouse models of HSAN. This has involved making in the mouse SPT gene the same mutations that cause HSAN in people. If all goes well, the resulting mice will have one normal copy of the gene and one mutated copy, which is exactly the balance of genes present in individuals with HSAN. In the transgenic model now in hand, there are two copies of the normal SPT gene and extra copies of an extra gene (the “transgene”) with the mutated SPT. This transgenic mouse will continue to be extremely informative in many studies. However, as we move toward testing gene silencing in mice, the improved mouse with one normal and one mutant gene will be very advantageous.
In efforts outside the laboratory, we have been working jointly with Dr. Eichler and the Massachusetts General Hospital team to continue the clinical trial and pursue other issues related to clinical evaluation of HSAN (such as developing biomarkers).
It cannot be over-emphasized that all of us in the HSAN research program are very fortunate to work closely with the Deater Foundation in these investigations. We look forward to another productive year in the laboratory and the clinic. We welcome the chance to help plan another outstanding workshop on HSAN. With the current rate of progress, we anticipate that the next HSAN conference will be timely and exciting, and another milestone on the path to finding a treatment.