Abstract
Professor Illana Gozes was interviewed by Emma Quigley (Senior Editor, Expert Opinion) on 17th April 2007.
Professor Illana Gozes BSc, PhD holds the titles of Professor of Clinical Biochemistry; The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Director of Adams Super Center for Brain Studies and Levi-Edersheim-Gitter fMRI Institute; Head of the Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Tel Aviv University and Chief Scientific Officer, Allon Therapeutics, Inc., Vancouver BC, Canada. Professor Gozes has served as a member (or chair) of several faculty, university or national and international committees and she currently serves on the Board of Directors of Allon Therapeutics, the Scientific Review Board of the ISOA, and is the Editor-in-Chief of the Journal of Molecular Neuroscience. Professor Gozes has received a number of scientific awards for her work including the Landau Award for an excellent PhD dissertation, the Juludan Prize and the Teva Founders Prize for exceptional scientific studies that may lead to biotechnology developments as well as the Bergmann Prize and the Neufeld award for outstanding/leading US-Israel BSF grant proposals, and has published extensively in the fields of molecular neuroscience and neuroprotection (> 200 scientific manuscripts). She is co-inventor of > 15 patents and applications, including the composition of matter patent on AL-108 and AL-208, Allon's lead compounds. Professor Gozes received a BSc from Tel Aviv University, a PhD from The Weizmann Institute of Science and was a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, Research Associate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior Scientist/Associate Professor at the Weizmann Institute and a Fogarty-Scholar-in-Residence at the National Institutes of Health (USA). Professor Gozes directs a very active research laboratory at Tel Aviv University and is mentoring and has mentored directly ∼ 50 graduate students toward their MSc or PhD degrees.
1. Can you explain the function of vasoactive intestinal peptide (VIP)?
A function of a peptide hormone can be measured by several methods including direct application of the peptide in a physiological system, peptide antagonism at the receptor level, downregulation at the level of the mRNA, gene knockdown or enhanced expression of the peptide. VIP displays many functions. It was discovered in the early seventies to be a potent vasodilator and its application in a physiological system resulted in increased cAMP formation and vasodilation. For the developing embryo, VIP was found to act as a potent growth factor, enhancing cell division. Among others, VIP blockade includes disruption of the circadian clock, inhibition of sexual activity and reduced cognitive function. It has since been found to be neuroprotective through glial cells. I assumed neuroprotective activity by analyzing gene expression patterns of VIP in the developing brain, while discovering enhanced VIP expression at the time of synapse formation. Concomitantly, Douglas E Brenneman discovered glial-mediated neuronal protection of VIP against electrical blockade. Together, we discovered novel proteins that are secreted from glial cells as a consequence of VIP activation and directly provide neuroprotection and growth factor activities.
2. What pathologies is this hormone involved in?
VIP is expressed in many different cancer cell lines, including lung, breast, pancreas and more. In terms of the growth factor activity, and depending on the cell line and culture conditions, VIP either enhances cancer growth or, under certain circumstances, inhibits cancer growth. This dual action may reside in part on the expressed receptor repertoire (with the two major VIP receptors being VPAC1 and VPAC2) and the downstream signal transduction pathways. VPAC1 receptors are present in high densities on human lung and breast cancer cells lines and biopsy specimens. In VIPoma, a type of cancer that secretes high levels of VIP, increased secretion of VIP leads to an increase in bowel movement, causing watery diarrhoea.
VIP has also been associated with asthma and poor bronchodilation. VIP is expressed in the sex organs both in males and in females where it has been associated with sexual function.
3. What are the therapeutic implications of targeting this hormone?
VIP (termed Aviptadil) is marketed by Senatek as an injectable therapy in combination with the adrenergic drug phentolamine and sexual stimulation for the treatment of sexual dysfunction in men.
Recently, Biogen Idec and mondoBIOTECH AG, announced the signing of an exclusive collaboration and license agreement for Biogen Idec to develop, manufacture and commercialize Aviptadil for the treatment of pulmonary arterial hypertension (PAH). mondoBIOTECH has been granted orphan drug designation for Aviptadil for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension by the European Agency for the Evaluation of Medicinal Products. Aviptadil as an inhalation treatment is in Phase II clinical trials in patients with primary pulmonary hypertension. Available clinical results are highly promising.
There are other indications that may involve VIP as an active drug product including acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Crohn’s disease or autoimmune diabetes. VIP can actually be used in these conditions to inhibit the autoimmune response.
In cancer, VPAC1 receptors may be molecular targets for diagnosis, prevention and treatment of breast cancer, as well as lung cancer. Radiolabelled VIP analogues have been developed for imaging of lung and breast cancer. Synthetic VIP receptor antagonists inhibited the proliferation and potentiated the ability of chemotherapeutic agents to cause apoptosis of lung and breast cancer cells. VIP-chemotherapeutic conjugates have been synthesized which bind to VPAC1 receptors and are internalized, resulting in the killing of lung and breast cancer cells (Moody TW and Gozes I: Curr. Pharm. Des. (2007) 13(11):1099-104)
4. What are you currently working on?
We are working on the development of VIP analogues with increased potency and bioavailability (e.g., Dangoor D et al.: Regul. Pept. (2006) 137:42-49) and on our portfolio of existing VIP analogues including lipophilic and hybrid VIP analogues developed together with Professor Mati Fridkin from the Weizmann Institute of Science.
My major interest is proteins downstream from VIP. We are working on two proteins: activity-dependent neuroprotective protein (ADNP) and activity-dependent neuroprotective factor (ADNF) and their respective active neuroprotective peptides (NAP and ADNF-9) derived by peptide activity scanning. ADNP and ADNF were discovered as glial (neuronal support cells) VIP-induced proteins, as a part of a long-term collaboration with Douglas E Brenneman and are exclusively licensed for development in neuroprotection, from Ramot at Tel Aviv University and the NIH to Allon Therapeutics, Inc. (where I serve as the Chief Scientific Officer and Scientific Founder).
I have recently reviewed ADNP (Gozes I: Pharmacol Ther. (2007) 114:146-154). ADNP is essential for brain formation and the gene encoding ADNP is highly conserved and abundantly expressed in the brain. ADNP mRNA and protein expression responds to brain injury and oscillates as a function of the estrus cycle. NAP, a derivative of ADNP, provides potent neuroprotection and is presently in clinical development for neuroprotection.
Allon Therapeutics, Inc., a clinical-stage Vancouver-based Canadian biotechnology company is at present developing two formulations of NAP as an active cognitive enhancer/neuroprotector. In cell culture, NAP has demonstrated protection against toxicity associated with the β-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle-aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs and functional behavioural assays in rats, no adverse side effects were observed with NAP concentrations that were ∼ 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer’s disease.
Allon Therapeutics periodically reports progress; for example, on 15th March 2007 it reported that the two formulations of NAP, the intranasal (AL-108) and the intravenous (AL-208) are currently in Phase II clinical trials. AL-108 is at present being evaluated in a Phase II efficacy trial as part of Allon’s Alzheimer’s programme in mild cognitive impairment. This trial is expected to complete enrolment at the end of 2007. It was also reported that AL-108 was recently selected by the National Institute of Mental Health funded project the Treatment Unit for Research of Neurocognition in Schizophrenia for another Phase II efficacy trial evaluating it as a treatment for schizophrenia-related cognitive impairment. Furthermore, the company received funding from The Michael J Fox Foundation for Parkinson’s Research to evaluate AL-108 in preclinical models as a potential treatment of Parkinson’s disease. The studies are under way and, if positive, Allon would be in a position to begin a Phase II clinical trial to evaluate the drug’s effectiveness in Parkinson’s disease patients as early as 2008. Allon also recently announced that AL-208 had progressed into the randomized portion of its Phase II human clinical trial evaluating it as a treatment for mild cognitive impairment that commonly occurs following coronary bypass graft surgery. This trial is expected to be completed in the second half of 2007.
There have been development steps in Allon’s pipeline based on the ADNF platform; AL-309 preclinical studies demonstrated that it had neuroprotective effects in several animal models of neurodegenerative disease. This product has robust oral bioavailability and also enters the brain. Effective concentrations can be detected for extended periods of time. These new results are quite significant as they show that AL-309 passes through two meaningful barriers to drug delivery: the intestinal wall and the blood–brain barrier. This information serves to confirm the potential of AL-309 as a highly novel CNS drug. This was reported by Gordon McCauley, President and CEO of Allon Therapeutics, Inc.
5. What is the mechanism of action?
A common characteristic found in patients with neurodegenerative conditions is the death of neurons, which can occur as a result of a breakdown of microtubules (cylindrical strands of protein). When the microtubule system breaks down, the axonal transport within a cell and the chemical transmission between cells is disrupted. This disruption causes neuronal death. NAP and related compounds prevent neuronal cell death by binding to neuron-specific tubulin, subsequently repairing the microtubular network. NAP and ADNF-9 promote neurite growth, which is dependent on microtubule formation. Numerous preclinical studies have shown that NAP and NAP formulations are safe and effective in treating a range of neurodegenerative conditions.
Further insights into the mechanism of action are active areas of research in my laboratory.
6. What is the future for research into VIP?
I think there is a requirement for better understanding as to the hormone-modulator action of VIP and downstream proteins, such as the ones I am working on right now, and the newly developed analogues as well. There are many areas in which VIP has a function. Furthermore, VIP is a member of the family that includes pituitary adenylyl cyclase activating polypeptide (PACAP), which is also associated with neuroprotection. Combinations of analogues of VIP and PACAP, in terms of neuroprotection, which is what I am most interested in, hold a promise for future therapeutics.
In terms of sexual function or cancer, one could look at the VIP receptor and try to inhibit cancer growth using agonists/antagonists to VIP. This is something we are also working on but it is more of a sideline.
As I mentioned, we (Allon Therapeutics, Inc.) are in Phase II clinical trials with our work in neuroprotection. This could have future applications in Alzheimer’s disease, Parkinson’s disease and any other diseases associated with damage to nerve cells. There could also be a use in acute diseases, such as stroke, where there is a need for neuroprotection.
7. Please provide your expert opinion
In terms of peptide therapeutics, the thing to take into account is that the molecules we are discussing are very small and highly efficacious. If you try to use large proteins as therapeutics they present disadvantages including rapid break down, limited bioavailability and expensive production lines. Smaller peptides are advantageous in all the abovementioned characteristics. I do think they hold much promise in terms of drug design and development. Other important factors are the formulation and innovative routes of administration. Travelling down the discovery lane that led to the finding of the VIP-regulated ADNP and ADNF should uncover additional neuroprotective mechanisms and potential drug candidates that may all act in concert to provide very potent neuroprotection.
In general, drugs that treat the symptoms and effects of neurodegenerative conditions and provide neuroprotection represent a rapidly growing market. Many of these illnesses are age-related and will have an increased impact over the next 20 years as the elderly population continues to grow. At present, therapeutic intervention in these diseases is focused on symptomatic treatment such as the cholinesterase inhibitors in Alzheimer’s disease. However, the preferred strategy to combat these diseases is neuroprotection, limiting neurological tissue damage and disease progression. Neuroprotective therapies for CNS injury are becoming a primary focus of both pharmaceutical and biotechnology industries. The indications include Alzheimer’s disease, with > 20 million patients in the developed world, Parkinson’s disease, multiple sclerosis, neuropathies, and degeneration resulting from acute injuries such a stroke, traumatic brain injury and cognitive impairment as a complication of coronary artery bypass surgery. All these devastating conditions have a great impact on individuals and society and will extensively benefit from scientific research and development toward neuroprotective therapeutics.