A-T Research and Therapy Pipeline

Transcription

1 L-Dopa (approved drug), ATCC, JHH Amantadine (approved drug), Nissenkorn 4-AP (approved drug), Shaikh/ATCC, JHH Baclofen (approved drug), ATCC, JHH Inositol (supplement), Berry ALA/Nicotinamide (supplements), ATCC GVT/MSL, Wong/BachPharma EUK-207, Malfroy/BioMarin DPUFAs, Retrotope Betamethasone (approved drug), Pignata/Kumada EryDex (approved in Italy), Chessa EryDex, EryDel (USA) ATM Lentiviral vector, Esteves ATM Lenti / transposon, Molina A-T hescs and ca-t hescs, Xu A-T ipscs, Lavin and others Ataxic (?) KO mouse, Proschel ATM missense and KO rat, Lavin A-T piglets, Pearce/Exemplar Primary PTC read through (RT) compounds, Gatti Splice altering compounds, Gatti PET/fMRI, Volkow DTI/PET, Rose MRI/MRS, Auer Inspiratory muscle training, Ross Exercise, Ross For FA A-T Research and Therapy Pipeline Approval Phase 3 Phase 2-Large Phase 2-Small Phase 1 Preclinical Development Research and Discovery Modulate neuronal transmission or circuitry Decrease oxidative stress Corticosteroid treatment Gene therapy Stem-cells Animal models with a neurological phenotype Mutationtargeted therapies Neuro-imaging Physical therapies

2 Modulate neuronal transmission or circuitry L-dopa A small study of this drug, which is used to treat Parkinson s disease, was carried out at the Johns Hopkins A-T Clinical Center in 1998 with mixed results. There is some interest in carrying out a larger study, perhaps focusing on people with symptoms arising from dysfunction of the basal ganglia or extra-pyramidal system, rather than pure ataxia. Amantadine Andrea Nissenkorn, of the Safra Children s Hospital, in Tel Aviv has conducted a small trial of amantadine sulphate, a drug similar to L-dopa, to treat ataxia and other neurological symptoms of A-T with reasonably positive results. She would like to conduct a larger scale trial. 4 A-P 4-Aminopyridine is a drug that has been used to treat the symptoms of multiple sclerosis and some other ataxias. A small-scale study is currently being set up at the Johns Hopkins A-T Clinical Center to evaluate whether there might be benefit in carrying out a larger study. Baclofen A study into the effects of this drug in improving eye movement and tremors in A-T was recently completed at the Johns Hopkins A-T Clinical Center. Results have not yet been published. Decrease oxidative stress Inositol A study was carried out in the late 1990s by Gerard Berry at the Children s Hospital of Pennsylvania. While there was no objective evidence of improvement in neurological or immunological symptoms, some parents reported improvements in mood or behaviour. ALA and Nicotinamide A study of the effects of nicotinamide and the anti-oxidant alpha-lipoic-acid was carried out in 2005 at the Johns Hopkins A-T Clinical Center. While there was an improvement in laboratory markers of oxidative stress and some improvement in lymphocyte counts there was no other significant clinical gain though the study did yield an accurate and reproducible means of measuring lung function in A-T. GVT/MSL EUK 207 DPUFAs, Bach Pharma, in association with Paul Wong of the MD Anderson Cancer Centre, University of Texas, is looking to organise a trial of Monosodium Luminol (MSL/GVT), a known drug with immune modulatory properties, in two to five year olds with AT. They would like to start a small Phase 1 study focusing on safety in July Bernard Malfroy-Carmine, of Mindset Rx, is looking to establish a clinical trial in children of the anti-oxidant drug EUK-207, the license for which is currently held by BioMarin. EUK-207 had an effect in treating the neuro-behavioural defect in A-T-null mice. Polyunsaturated fatty acids (PUFAs) are essential to cells in the nervous system, but are susceptible to oxidative damage, possibly leading to neurological deterioration. The company Retrotope is attempting to stabilize the PUFAs and protect cells from this

3 oxidative damage by using mimetics (very similar chemical substitutes) of PUFAs known as DPUFAs (deuterated PUFAs). They are hoping to start a trial DPUFAs in patients with Friedreich s Ataxia in If successful, it may be possible to establish a trial in patients with A-T. Cortico-steroid treatment Luciana Chessa, Sapienza University, Rome, conducted a small-scale trial (non-placebo controlled) of dexamethasone delivered via infusion into the patients own red blood cells. Around half of those tested responded to the treatment and had a positive benefit. The company that has a patent on this mode of treatment has just got approval from the United States FDA for its machine and is planning to organize a Phase I trial in the USA. An international group including Luciana Chessa (above), William Whitehouse, Nottingham University Hospitals, and Kate Sinclair, Royal Brisbane Children s Hospital are seeking funding for a 3-centre efficacy trial of low-dose oral betamethasone, to follow up the encouraging results of a very small scale study in Italy. Satoko Kumada, Tokyo Metropolitan Neurological Hospital, is also undertaking a small-scale study of betamethasone in A-T. Gene therapy Miguel Esteves, University of Massachusetts Medical School, has developed a lentiviral vector for the A-T protein (ATM) is now assessing the most effective way to test this vector. Ignacio Molina, University of Granada, has received a grant from the joint fund established by the A-T Society, Action for A-T and Sparks for a gene therapy project. He has developed lentiviral vector for an ATM minigene and is working to see if the minigene can express a fully functioning protein. Dr. Molina is also attempting to resolve difficulties in producing large quantities of the vector. Stem-cells Yang Xu, University of California, San Diego, has developed both a line of ATM-null human embryonic stem-cells (hescs) and a line of conditional hescs, in which the functioning of ATM protein can be switched on and off. Martin Lavin, Queensland Institute of Medical Research has generated both induced pluripotent stem cells (ipsc) from patient fibroblasts and olfactory neurosphere derived stem (ONS) cells from patient olfactory mucosa. They have characterised both cell types and demonstrated that they can be differentiated into functional neurons, thus representing a useful resource for further study of the pathogenesis of A-T for screening potential therapeutics.

4 Animal models with a neurological phenotype Margot Mayer-Proschel, University of Rochester, USA, has developed a strain of ATM knockout mice (ATM fl/fl x CMVcre), which appear to display a clear neurological phenotype whereas other strains of ATM knockout mice do not do so. The low number of mice bred so far means these mice require further characterization and work continues. Martin Lavin, Queensland Institute of Medical Research, is developing colonies of rats with both ATM-knockout and missense mutations. Both strains appear to show neurological deficits, but irregularly, and work continues. David Pearce and Exemplar Genetics in the USA are working to develop an ATM-knockout pig, with the aim of generating a neurological phenotype more similar to that in humans. Heterozygote piglets (carriers of one knock-out gene) have been made but as yet, no homozygotes.(with two knock-out genes) have been produced. Mutation-targeted therapies Richard Gatti at UCLA has been working for some years on identifying small molecules that will enable cells to read through a particular kind of mutation known as a nonsense mutation (sometimes also stop codon or primary premature termination codon ). Some promising compounds have been identified, and Dr. Gatti is trying to find a pharma company willing to invest in the extremely expensive process of developing the drugs for clinical trials in humans. Around half of all A-T mutations are so-called splicing mutations. Richard Gatti has demonstrated that chemical compounds called splice-switching oligoneucleotides have the ability to restore gene expression (hence the production of functioning ATM protein) in ATM deficient cells in the laboratory. Neuro-imaging Norah Volkow, Brookhaven National Laboratory, New York, is carrying out a study using PET scanning and functional MRIs to study brain metabolism and functional interaction between brain cells in adult patients with A-T. Much data has been gathered and is being elaborated (or analysed ), but early results show very interesting variations from the scans of non-a-t control subjects. Dr Stephen Rose, at the University of Queensland, is leading a programme involving scans of the brains of young patients with A-T. He is examining cerebellar white matter motor pathways using diffusion MRI and neuro-inflammation using PET scans. The study aims to improve our understanding of the how neurodegenerative processes affect individuals and to identify neuro-imaging biomarkers for future therapeutic interventions. Dorothee Auer, at Nottingham University, is seeking funding for a project to use Functional MRI and MR spectroscopy to develop biomarkers for measuring neurodegeneration and for identifying and monitoring the mechanism of action of anti-oxidant therapies. This study would complement the two outlined above.

5 Physical therapies Emma Ross, at the University of Brighton, is studying whether breathing training delivered via a hand-held inspiratory muscletraining device improves lung function, cough effectiveness and quality of life in individuals with A-T. Although the benefits of exercise are well documented, no studies have investigated the effect of an exercise intervention in people with A-T. In this project, Dr Ross aims to examine if exercise can improve muscle function and movement coordination, which will in turn improve the ability to perform daily tasks, increase confidence and psychological wellbeing. Produced March 2013 by the A-T Society and the A-T Children s Project