• The end and yet hope finds its place in an unusual condition 15 January 2018 | View comments

  • 15th January 2018 | By David Jolley

    John R pointed to me a report carried by The Telegraph announcing Pfizer’s decision to pull out of Alzheimer’s research. Massive investment over many years has produced nothing worthwhile.  http://www.telegraph.co.uk/science/2018/01/08/hunt-alzheimers-cure-suffers-heavy-blow-pfizer-pulls-research/

    Within days The Guardian was confirming negative findings from the latest Lundbeck trial: https://www.theguardian.com/society/2018/jan/09/alzheimers-setback-as-promising-drug-shows-no-benefit-in-clinical-trials-idalopirdine

    We reflect on the debate at the Dementia Congress in Doncaster last November – this concluded that more should be spent on improving care and preventative strategies – less on the largely unproductive biological research. There is congruence here.

    A dreadful headline in the Manchester Evening News tell of horrifying profiles of the regime in one ‘Care’ Home. http://www.manchestereveningnews.co.uk/news/greater-manchester-news/care-home-where-pensioners-were-14142279

    We note the report that Lady Lucan is believed to have killed herself for fear of developing Parkinson’s Disease.

    We are encouraged to find additional research confirms the positive benefits of time with nature: https://inews.co.uk/news/health/urban-city-walk-trees-birds-mental-health/

    But the thing which caught my eye was the headline: ‘Excitement as trial shows Huntington drug could slow progress of the disease’: https://www.theguardian.com/science/2017/dec/11/excitement-as-huntingtons-drug-shown-to-slow-progress-of-devastating-disease

    This report draws attention to work by Professor Sarah Tabrizi and colleagues at University College London. It made me go back and revise my memory of Huntington’s disease – otherwise and originally Huntington’s Chorea.

    This condition has been known by descriptions certainly to the Middle Ages and maybe before. But it was 1872 that George Huntington, a physician in Pennsylvania, wrote the classic paper which captured its clinical features and its inheritance pattern as a dominant gene abnormality. He traced families in America who were all descended from a family which had come to Boston in the 1660s. They came from the Suffolk village of Bures. Bures is not far from Colchester, where I worked as a student. It was there that I first heard about the disorder and met a patient.

    The clinical picture is of a neurodegenerative disorder which affects the sexes equally and usually shows itself in middle life, though onset in later life or early adult life is also known. Huntington described the onset of choreiform movements, loss of coordination and balance. In addition, subjects experience deterioration in cognition and develop a dementia syndrome with frontal lobe features. Psychiatric symptoms, particularly irritability are common. A notable feature is a much-increased suicide rate. Loss of weight, endocrine abnormalities and sleep disturbance emerge as the condition progresses. Eventually subjects will become bedfast and die after a period of maybe ten years or more, of inanition or intercurrent infection.

    More recent studies have found that the gene fault is located on the short arm of chromosome 4. It is now understood that the flaw is at the Huntingtin locus: this codes for the protein huntingtin which is essential for nerve cell growth and maturation. A sequence of the nucleotides Cytosine, Adenine and Guanine (CAG) in the DNA of the chromosome caries the information to form this. There are repetitions of the CAG sequence needed to produce healthy huntingtin, but in Huntington’s Chorea the number of repeats is excessive and results in the production of a toxic version of huntingtin. Normal people may have up to 36 repeats of the CAG sequence. 36 to 39 repeats make the emergence of Huntington’ Chorea possible and a greater number of repeats make it inevitable. The larger the number of repeats, the earlier the age of onset of the condition.

    It has been possible to test for the presence of the abnormal gene for some years. This poses complex ethical and practical issues for individuals, families and professions. These have been well reviewed by Professor Tabrizi and her colleague Marianne Novak http://www.bmj.com/content/340/bmj.c3109

    The breakthrough is the production of a synthetic DNA strand Ionis-HTTRx which binds to mRNA, which would inform the production of the rogue huntingtin (like Lego!), and neutralises it. Research involving treatment of 46 individuals, who were demonstrating early signs and symptoms of Huntington’s Chorea, across the UK, Canada and Germany has confirmed that levels of huntingtin in their cerebrospinal fluid (CSF) was reduced. The substance has to be injected into the cerebrospinal space at monthly intervals – so it is a highly skilled activity and not without some risk. Thus far it is not possible to say whether the change in concentration of will achieve worthwhile clinical changes. It would be an expensive mode of treatment.

    Similar research has led to the establishment of effective treatment for other genetically programmed illnesses: spinal muscular atrophy www.ncbi.nlm.nih.gov/pubmed/28884620 and retinitis pigmentosa http://ir.sparktx.com/news-releases/news-release-details/fda-advisory-committee-unanimously-recommends-approval are examples.

    Costs are prohibitively high – of the order of one million dollars per individual – and treatment techniques are complicated. It may be that we are making discoveries which show what can be done – but it seems the ethics and economics of such treatments, if they were to be prepared for more common conditions such as Alzheimer’s disease of Parkinson’s disease, will mean that they are not feasible.

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