One of the strongest and most persistent trends in medical care is the transition from invasive medical procedures, such as open surgery, to minimally-invasive interventions that typically result in faster procedures with less patient trauma and better outcomes. New minimally-invasive interventions may also enable the treatment of conditions for which no adequate therapy is currently available. Imaging and related technologies are key to guiding minimally-invasive procedures, providing visualization of the target area for treatment, assisting in the proper placement and operation of instruments, and monitoring the progress of the intervention. In order to optimally perform such interventions, image guidance, novel interventional instruments and advanced therapy solutions are required. Philips Research and GlyGenix Therapeutics will research the feasibility of using ultrasound technologies to guide, monitor and control the delivery of therapeutic DNA to the liver in preclinical studies for the treatment of Glycogen Storage Disease Type 1a (GSD-1a). For Philips, involvement in this joint research work is one of a number of partnerships that will exploit its advanced focused-ultrasound technology. In addition to using co-injected microbubbles to induce sonoporation, it is also exploring the possibility of using focused ultrasound to release drugs from drug-loaded microbubbles and nanoparticles to achieve targeted drug delivery, and the possibility of using it for thermal ablation therapy. These initiatives include Philips’ leadership of the European Union (EU) SonoDrugs project. Glycogen Storage Disease Type 1a
Glycogen Storage Disease Type 1a (GSD-1a) is caused by a defective G6Pase gene that prevents the body from producing an enzyme called glucose-6-phosphatase. This enzyme plays a critical role in the conversion of glycogen to glucose in the liver as the body attempts to maintain an adequate blood sugar level between meals. Absence of the enzyme can therefore lead to potentially life-threatening periods of acute hypoglycemia (severely reduced blood sugar). Because the defective gene only impairs the body’s ability to convert glycogen into glucose and not its ability to convert excess glucose into glycogen, the disease also results in excessive glycogen storage – hence the name Glycogen Storage Disease. This typically results in enlargement of the liver, kidneys and small intestine, often with a range of other debilitating comorbidities. At present, GSD-1a is only managed, not cured. Disease management normally involves stringent dietary regimes to ensure that the body has a continuous but not excessive supply of glucose from dietary sugar and starch. This therapy often involves continuous feeding via nasogastric or gastrostomy tubes, or regular feeding every few hours throughout the day and night. Because treatment must be carried out from a very early age, the disease is particularly distressing in infants and children. GSD-1a is an inherited disease, with children born to parents who are both carriers of the defective G6Pase gene having a one-in-four chance of suffering from it. Although GSD-1a is a rare disease, currently affecting around 1 in every 100,000 to 200,000 births in the USA, its debilitating nature and impact on quality of life make it a disease that demands worthwhile specialist effort to find better treatments. Curative gene therapy
One potential cure for GSD-1a is gene therapy, in which non-defective G6Pase gene is introduced into liver cells in the form of a plasmid (a typically circular DNA molecule that is capable of independent replication). By restoring production of the glucose-6-phosphatase enzyme in GSD1a patients, the rigid dietary regimen and associated complications are eliminated, leading to a cure for the disease. The challenge is to find a way of delivering the G6Pase gene to liver cells. One method that has been explored is to use viral vectors to transport the gene into the cells. Candidate viruses do exist, such as the adeno-associated virus (AAV). However, current gene therapies that use viral vectors to infect cells may carry the risk of an antiviral immune or inflammatory response. Ultrasound-mediated gene delivery
Ultrasound-mediated delivery of genes offers an attractive alternative that overcomes the concerns associated with viral vectors and also provides opportunities to non-invasively target therapy at specific internal organs. The ultrasound technique that will be investigated by Philips and GlyGenix Therapeutics, Inc. relies on a process called sonoporation. Sonoporation involves the use of microbubbles (microscopic gas-filled spheres made of a biocompatible material such as phospholipid) that will be co-injected into the bloodstream along with the G6Pase gene. Because these microbubbles act as an ultrasound contrast agent, their arrival in the liver (and by inference, the arrival of G6Pase at the liver) can be tracked with an ultrasound scanner. When they arrive at the liver, the microbubbles will then be subjected to high-energy focused ultrasound pulses at their resonant frequency, causing them to rapidly expand and contract. If the microbubbles are close to a cell wall, their physical deformation or fragmentation increases the porosity of the cell wall to the G6Pase gene. The exact mechanisms involved are not yet fully understood, but it may be that the oscillating microbubbles induce cavitation or microscopic water jets in the surrounding fluid, while fragmentation of the microbubbles may create ballistic fragments that pierce the cell walls. In this application, the microbubbles therefore act as both an imaging agent for guided intervention and as a delivery mechanism for non-invasive therapy. The same ultrasound scanner will also be used to image the liver during the procedure. Partnering for success
As with most rare diseases, clinical expertise on GSD-1a is concentrated in only a few medical centers around the world. Philips and GlyGenix Therapeutics are therefore fortunate in being able to conduct pre-clinical studies in collaboration with the Division of Medical Genetics at Duke University (Durham, North Carolina, USA), which currently manages the treatment of many GSD-1a patients. This should make it significantly easier to move from pre-clinical to clinical trials if the results of the joint research look promising. |