TRIUMF’s Nuclear Medicine group has recently been awarded an NSERC Engage grant to support a new collaboration with B.C.-based biotechnology start-up ImStar in the development of a promising new therapeutic drug for the treatment of Amyotrophic Lateral Sclerosis (ALS). The Engage grant, which is designed to jump-start new interactions between academic and private-sector partners, will fund the first step of larger collaboration that will leverage TRIUMF’s medical imaging expertise to investigate the new drug’s in vivo behaviour.
ImStar has developed a novel therapeutic drug candidate that holds potential for the treatment of ALS (also known as Lou Gehrig’s Disease), a debilitating neuromuscular disease which currently has no effective treatment or cure. The drug compound is derived from withaferin A isolated from the winter cherry plant, which has been shown to have a neuroprotective effect in animal models of ALS. However, during preclinical studies, ImStar scientists observed a disconnect between the pharmacokinetic profile of the drug (where it travels and how long it remains in body) and its therapeutic effect. When the drug was administered, it appears to rapidly clear from the blood; however, a therapeutic effect was evident for days. ImStar needs more information to improve their understanding of where and how long the drug is active in the body.
This is where TRIUMF’s Nuclear Medicine team comes in, with their extensive experience in radiochemistry and medical imaging. TRIUMF will create a radioactive copy of ImStar’s drug candidate, which will (at a later date) be injected into a preclinical model and imaged by PET scan in order to gain a complete picture of the drug’s behaviour in the body.
“It’s a good marriage between the chemistry that we’re capable of and the needs of a start-up company,” explains Paul Schaffer, head of TRIUMF’s nuclear medicine division. “We’re able to offer the data they need to help their development effort.”
The NSERC Engage grant will fund the first step of this collaboration, which is the radiochemistry behind the creation of the radioactive equivalent drug. TRIUMF scientist Dr. Qing Miao is leading the effort to radiolabel the current drug using Carbon-11. The radiochemistry for duplicating a drug compound is complex; however in this case there are a few specific challenges Miao faces. The 20-minute half-life of Carbon-11 puts a time constraint not typically encountered with organic synthesis using stable isotopes (i.e. carbon-12).
In this instance, such a short half-life allows for only one or two very rapid synthesis steps in the process of making the final product. Adding to the challenge, the withanolides are complex natural products with multiple reactive regions of the molecule which could undergo unwanted side-reactions, creating complex and unusable mixtures. Thus, the reactivity of one site of the molecule must be artificially blocked in order to allow radiolabelling to occur.
The short half-life, as well as the limited amount of available material, prevents the use of traditional chemical techniques to characterize the molecule. Instead, the carbon-11 compound will be compared against data on ImStar’s original drug, using a suite of alternative techniques located at TRIUMF. This will ensure that the two drugs are the same chemically - which means that they will behave identically in vivo.
The final deliverable in the Engage grant will be to make this compound into a pure, biologically compatible formulation that is ready for injection. Eventually, the ultimate goal of the collaboration is to image the radiolabelled compound in a preclinical model, gaining a clear understanding of the drug’s behaviour in the body, including where, when, and how long it circulates and whether it can cross the blood-brain barrier.
This information will be crucial to ImStar’s drug development effort, bringing their potentially breakthrough therapeutic drug candidate one step closer to patients - with the help of TRIUMF’s nuclear medicine team and initial support from the NSERC Engage grant.
–Prepared by Lindsay Kroes, Communications Assistant