Small molecule and protein-based neurotrophic ligands: agonists and antagonists as therapeutic agents
Authors: Saragovi H.U.1; Burgess K.2

Source: Expert Opinion on Therapeutic Patents, Volume 9, Number 6, June 1999, pp. 737-751(15)

Publisher: Informa Healthcare



The neurotrophins are proteins of a growth factor family that affect the survival, growth and/or differentiation of neurones and several other populations derived from the neuroectoderm. Neurotrophins and their receptors are important targets for therapy of human disease, with potential applications ranging from treatment of chronic or acute neurodegeneration, to pain or cancer. Several neurotrophins have been used clinically. However, they are poor pharmacological agents because of drawbacks inherent to proteins when used as drugs. Consequently, several pharmacological agents and approaches have been patented to exploit these important targets. Amongst the pharmacological agents that do not act directly via neurotrophin receptors we include those that modulate or induce local expression of neurotrophins, immunophilins and other agents with neurotrophic-like activity. These are usually agonistic agents. Amongst compounds that bind to and act via neurotrophin receptors we include peptide analogues and peptidomimetics of neurotrophins of anti-neurotrophin receptor antibodies. These agents can be agonistic or antagonistic. Other approaches involve antagonists of the neurotrophins themselves, usually large receptor-derived peptides as decoy docking sites. Small molecule, non-peptide synthetic agonists and antagonists of either neurotrophins or neurotrophin receptors will be valuable therapeutic agents for diseases that have markets worth billions of US dollars. Consequently, it is not surprising that some patents have made similar claims both in compositions of matter and in indications.

Keywords: Alzheimer’s disease; drugs; ligand; nerve growth factor; neurodegeneration; neuroectoderm; neurotrophin; immunophilins; pain; Parkinson’s disease; peptidomimetics; receptor; stroke; therapy; tumour

Document Type: Review article

Affiliations: 1: McGill University, Montréal, Quebec, H3G 1Y6, Canada. uri@pharma.mcgill.ca 2: Department of Chemistry, Texas A&M University, College Station, TX-77842-3012, USA. burgess@mail.chem.tamu.edu

Pill Stimulates CNS Neurons' Regrowth
Kenneth Bender
URL: http://www.psychiatrictimes.com/arti...leId=185300964

April 1997, Vol. XIV, Issue 4


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Orally active compounds called neuroimmunophilins were demonstrated to protect and to stimulate the regeneration of brain cells in animal models with Parkinson's disease, according to a study published in the March 4 issue of the Proceedings of the National Academy of Sciences.


The study was written by Joseph Steiner, Ph.D., and colleagues in the neurobiological research and medicinal chemistry departments of Guilford Pharmaceuticals, and communicated by Solomon Snyder, M.D., department of neurosciences, Johns Hopkins University School of Medicine. These researchers found that the experimental compound GPI-1046 exerted potent neuroprotective effects for nigrostriatal dopamine neurons exposed to the concurrently administered neurotoxin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). When the neuroimmunophilin was administered up to one month after an ablative course of either MPTP, or another neurotoxin, 6-OHDA (6-hydroxydopamine), it promoted regenerative sprouting in the few nigrostriatal neuronal fibers remaining intact (Steiner and colleagues).


Snyder, who described the neuroimmunophilins and their potential at the annual meeting of the American College of Neuropsychopharmacology (ACNP) in December, related to Psychiatric Times that these compounds "represent the first instance of agents that make damaged nerves grow back with restored function."


Peter Suzdak, Ph.D., vice president of research at Guilford and a coauthor of the Proceedings report, had previously commented on the investigation at the November meeting of the Society for Neurosciences. "The results obtained with GPI-1046 are to our knowledge unprecedented and the first-ever demonstration of a nerve regenerative effect with an orally active small molecule," he said. "I know of nothing which has previously demonstrated both such a potent regenerative effect on damaged brain neurons and a near normalization of animal behavior as we have shown with GPI-1046."


The development of the novel neuroimmunophilin compounds was based on observations that the "immunophilin" receptor proteins for immunosuppressant drugs like cyclosporin A (Sandimmune) are 10- to 50-fold more abundant in the nervous system than in immune tissue; and that increased mRNA expression of an immunophilin (FKBP-12) following a neural lesion occurs with enhancement of a protein (GAP-43) that has been associated with neurite extension. Following the determination that immunosuppressant drugs, affecting GAP-43, also enhance neurite extension, researchers then developed a series of compounds as ligands of the FKBP-12 immunophilin receptor protein that exert potent neurotrophic activity without suppressing the immune system.


Steiner commented on the activity of these compounds. "One of the most striking features of the neurotrophic actions of these neuroimmunophilin ligands is their efficacy and potency. GPI-1046 has produced significant enhancement of neurite outgrowth in sensory ganglia at concentrations as low as 1 picomolar. This means its neurotrophic potency is greater than that of nerve growth factor itself." Steiner and colleagues cited comparative data in the report which indicate that GPI-1046 is more potent in regenerating striatal dopaminergic markers after MPTP than epidermal growth factor, nerve growth factor, glial cell line-derived neurotrophic factor, and gangliosides or their synthetic derivatives.


Craig Hamilton, Ph.D., second author of the study, added, "Another potential advantage of GPI-1046 is that it is orally active and crosses the blood-brain barrier. Thus, it should not be limited by the drug delivery problems associated with protein and peptide growth factors." (Cerebroventricular infusions of nerve growth factor for Alzheimer's disease were described in Psychiatric Times, August 1994, p5.)


An additional important distinction from many neurotrophic polypeptides is that the immunophilin ligands do not appear to induce aberrant sprouting of neuronal processes when administered to normal animals. Steiner and colleagues wrote, "In normal rats and mice, we have carefully examined sciatic and facial nerves as well as numerous areas of the brain and spinal cord and failed to observe any suggestions of abnormal sprouting."


In this current report, the researchers described GPI-1046 stimulating partial morphological recovery in animal sciatic nerve fibers following crush injury, and in central serotonin neurons following parachloroamphetamine (PCA)-induced lesions. In a model of Parkinson's disease in mice, nigrostriatal neurons are destroyed by MPTP-induced oxidative free radical mechanisms. The protective effects of GPI-1046 were demonstrated in this model when concurrent administration of the neuroimmunophilin and MPTP spared more than twice the number of striatal dopamine neurons compared to controls exposed to MPTP/vehicle.


In a paradigm more closely fashioned to clinical remediation of a preexisting disorder, the researchers then administered GPI-1046 well after the maximal destruction of dopamine neurons by neurotoxins. The regenerative properties of the compound were evidenced by two- to threefold higher striatal innervation densities in treated animals than in the MPTP/vehicle controls. A similar recovery was achieved after neuronal destruction by 6-OHDA, with an approximate 30% restoration of striatal dopamine compared to controls. The reinnervation stimulated by GPI-1046 was described as "many clusters or small branches of processes emerging from the sparse network of spared nigrostriatal fibers, suggestive of terminal and collateral sprouting."


In addition to morphological and biochemical neuronal restoration, the researchers reported achieving functional recovery in these neurotoxic animals which, prior to receiving the neuroimmunophilin, had exhibited functional deficit behavior in apomorphine or amphetamine-induced rotational movements. This success, along with restoring approximately 30% of striatal dopamine "fits," the researchers note "with abundant evidence that only about a third of normal dopamine innervation is required for physiologic motor activity."


The portent of these results and the potential of these new compounds were enthusiastically described by Guilford CEO, Craig Smith, M.D. "Based on our experiments to date," he said, "we are actively investigating our neuroimmunophilin ligands as potential treatments for a range of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, traumatic head and spinal cord injuries, stroke and peripheral neuropathies such as diabetic neuropathy."


References

1. Snyder SH. Novel neural messengers: therapeutic implications. Presented in symposium, From the Bench to the Bed (Office) Side: New Directions for Preclinical Models of Clinical Symptoms and Drug Development, at the 35th Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Dec. 9, 1996.


2. Steiner JP, Hamilton GS, Ross DT, et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci. 1997;94:2019-2024.

Continuing the Work on Parkinson’s Research
Media Contact: Allison Elliott, (859) 257-1754

LEXINGTON, Ky. (Sept. 13, 2005) − The University of Kentucky Morris K. Udall Parkinson’s Disease Research Center of Excellence has been awarded nearly $6 million from National Institutes of Health and National Institute of Neurological Disorders and Stroke to continue work on the promising drug glial cell line-derived neurotrophic factor (GDNF) and similar compounds.

Greg Gerhardt, Ph.D., professor, Department of Anatomy and Neurobiology and Department of Neurology, director of the Morris K. Udall Parkinson’s Disease Research Center of Excellence, and director of the Center for Sensor Technology, has headed the Udall Center at UK since its inception six years ago. As one of only 12 Udall Centers in the nation, UK’s center represents the leading edge of research into Parkinson’s disease, which at this point remains an incurable condition. GDNF differs from other Parkinson’s therapies in that it has demonstrated potential to halt or perhaps reverse the neurodegenerative condition. Current treatments only provide temporary relief from symptoms.

"The NINDS is pleased to continue the support of the University of Kentucky Udall Center, a unique component of the Udall center program that provides non-human primate studies of potential therapeutics in Parkinson's disease," said Diane Murphy, Ph.D., Program Director for the NINDS' Morris K. Udall Parkinson's Disease Research Centers of Excellence.

Gerhardt and colleagues will spend the next five years investigating potential negative effects of GDNF, and how to fine tune dosing and administration techniques to make the therapy a safer and more viable alternative.

The $6 million funding from NIH represents a vote of confidence for the UK Udall Center and its work to date on GDNF and related molecules. At the end of this five-year funding cycle UK researchers plan to be ready to move GDNF or a related compound once again into human clinical trials – a timetable considered ambitious by industry standards, but realistic to Gerhardt.

UK’s research into GDNF made headlines recently when the CBS news show “60 Minutes” broadcast a feature on the controversy that arose when Kentucky and New York patients enrolled in a national Phase 1 clinical trial for the drug were left without medical treatment or legal recourse when Amgen, Inc., the biotech firm that holds the patent for GDNF, suddenly withdrew the drug from testing amidst allegations of safety and efficacy concerns.

Amgen’s own bioethicist told CBS that the decision was largely a result of a nervous pharmaceutical industry haunted by the specter of the Vioxx lawsuits. CBS also uncovered video footage in which an Amgen executive stated that the treatment in its current incarnation, a complex procedure involving deep brain surgery, would not be a money maker for the corporation. Shortly after halting the trial and withdrawing all GDNF treatment from patients, Amgen applied for a new patent on a different form of GDNF that could potentially be delivered in a more economical capsule form.

Despite the requests of investigators, the pleas of patients and the approval of the Food and Drug Administration, Amgen has refused to provide the drug under compassionate use guidelines to those patients who had undergone surgery to implant a pump and catheter in their brains, and had been receiving GDNF successfully for as long as two years. Court cases in Kentucky and New York have been dismissed and appeals are being considered.

While distinctly troubled by the plight of patients caught in the crossfire of the first GDNF trials, Gerhardt says Parkinson’s researchers are far from giving up all hope in GDNF. He continues to work with the drug in animal models, and to explore similar molecules to which Amgen does not possess patent rights. By exploring multiple paths of research at once, Gerhardt and his colleagues are applying the old maxim “don’t put all your eggs in one basket,” to the newest science imaginable.

“History is riddled with examples of technology that failed more than once before being perfected. The Wright brothers crashed a few airplanes. GDNF has not failed so spectacularly, although we still have much to learn about it. We’re going to spend the next five years studying the technology and how to translate it into clinical use in patients,” said Gerhardt.

The GDNF trial launched at UK in 2002, and was headed by principal investigator John Slevin, M.D., professor in the UK Department of Neurology and Department of Pharmacology and director of the Movement Disorders Clinic at UK; Gerhardt; Don Gash, Ph.D., the UK Alumni Chair in Anatomy and Neurobiology, professor in the Department of Anatomy and Neurobiology, and director of the M. Margrite Davis-Ralph E. Mills Magnetic Resonance Imaging and Spectroscopy Center at UK; Byron Young, M.D., the Johnston-Wright Endowed Chair of Surgery, professor, Department of Surgery, and chief, Division of Neurosurgery, associate dean for Clinical Affairs, and chief of staff, UK Hospital. Ten patients participated in the trial through UK, joining approximately 40 others in the United States and the United Kingdom.