Nucleic Acid Nanoparticles for Treating Human Diseases
Parkinson's Disease (PD)
PD is a progressive disease of motor control regions in the midbrain that result in injury and death to dopaminergic neurons, producing resting tremor, rigidity, lack of movement (bradykinesia), postural instability, and trouble initiating motion and/or stopping motion once it has begun. Other symptoms include slurred speech, loss of sense of smell, depression, fatigue, and constipation. Later PD symptoms include thinking disorders (dementia). The motor symptoms often represent the primary cause of PD morbidity. About 50,000 new patients are diagnosed yearly in the US, with a US total PD population of about 500,000.
Initially, PD motor symptoms are reasonably treated with dopamine neurotransmitter replacement therapy, such as levodopa. However, levodopa does not alter the progressive loss of midbrain dopaminergic neurons, eventually the medication becomes less effective, and also causes a variety of uncontrolled motor symptoms (dyskinesias). When oral medications fail to adequately control motor symptoms, neurosurgical implantation of deep brain stimulators in motor control areas of the brain may be helpful. Prior unsuccessful therapies include fetal cell transplantation studies, which produced dyskinetic side effects. An active area of research is to better define the type of neural stem cell that may produce new dopaminergic cells after brain transplantation. Controversial results were obtained in several PD clinical trials in which glial cell line-derived neurotrophic factor (GDNF) protein was infused by in-dwelling catheter into the midbrain, with multiple PD patients reporting significant improvement in motor function. Nevertheless, a larger study sponsored by Amgen failed to reproduce these results. Another class of PD therapy under development is viral-based AAV vectors to produce dopaminergic neurotransmitter synthetic enzymes or dopaminergic neuron supportive factors, such as GDNF or the related neurturin. A phase II trial of AAV vector expressing neurturin, sponsored by Ceregene, failed to meet its primary motor control endpoint (time interval off oral meds), another secondary motor endpoint was achieved but future development of the product stopped.
In association with the laboratory of Dr. David Yurek at the University of Kentucky , Copernicus DNA NPs encoding either rat or human GDNF have been quite successful in treating rats using a standard PD model in which dopaminergic neurons are injured and killed after exposure to a toxin, 6-hydroxydopamine. Direct injection of GDNF DNA NPs into the rat midbrain significantly reduced dopaminergic cell injury as evaluated by presence of a key dopamine production enzyme (tyrosine hydroxylase) and by multiple complementary assays of motor function, all of which were significantly improved. In a second series of studies, GDNF DNA NPs significantly increased survival of transplanted fetal neural stem cells into the lesioned midbrain (about a 10-fold increase in survival), demonstrating that DNA NP gene therapy can significantly augment the potential of neural stem cell transplantation therapy for PD. In studies supported by the Michael J Fox Foundation and NIH, the human GDNF gene sequence has been optimized to efficiently produce human GDNF protein in the rat brain. This represents a significant milestone in our pre-clinical drug development program for PD. In summary, we view GDNF NPs to be a candidate stand-alone therapy for PD, with potential to halt the progression of this chronic disorder, a capability not embraced by any of the marketed PD therapies. We also appreciate that GDNF NPs have the potential to greatly increase the effectiveness of neuronal stem cell transplant therapies; such a combined approach has the potential to introduce new dopaminergic neurons in the midbrains of PD patients, and may dramatically improve motor function.
In conjunction with the lab of Dr. Barbara Waszczak at Northeastern University , we recently published that administration of Copernicus DNA NPs into the nose (intranasal) results in widespread brain transgene protein expression, representing a non-invasive method to introduce therapeutic genes into the brain, effectively crossing the blood brain barrier. In PD model studies evaluating our optimized human GDNF NPs, Dr. Waszczak has found that intranasal administration of GDNF NPs protected dopaminergic neurons from the 6-hydroxyamine lesion. These ongoing studies may demonstrate that PD can be treated with our technology using a non-invasive dosing regimen, a remarkable achievement compared to competing viral-based vector approaches. Further optimization of several parameters, including the intranasal dosing regimen, NP structure, and GDNF expression control regions will determine the true potential for this important new discovery. A joint patent application with Northeastern University has been filed to cover the method of introducing Copernicus nucleic acid NPs into the brain via intranasal administration, including NP therapy for diverse brain disorders, including PD, Alzheimer's disease, stroke, multiple sclerosis, traumatic brain injury, and many others.
Before initiating clinical trials for Parkinson’s disease or other CNS diseases, Copernicus will need to further test the utility of the intranasal route of administration versus the direct injection route to assess which will be selected for completing pre-IND studies, including formal toxicity studies. Copernicus anticipates it will complete an initial clinical trial before intensely seeking a large corporate partner to fund the full development program.