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Hospital Peer Review: Revolution in Genetic Disorders
Revolution in Treatment of Genetic Disorders
Professor Julian Gillmore, UCL National Amyloidosis Centre
The development of an investigational therapy which ‘edits’ a harmful gene in patients with a debilitating condition called amyloidosis could pave the way for a revolution in the treatment of genetic disorders, finds a new study led by University College London scientists.
People with hereditary transthyretin (ATTR) amyloidosis have a mutation in the transthyretin (TTR) gene, which means they produce an abnormal protein that gradually builds up in the heart and nerves. Symptoms include numbness in the hands and feet, loss of control of the bowel and bladder and immobility. The condition gets progressively worse and is ultimately fatal. Amyloidosis is a rare disease caused by abnormal deposition and accumulation of proteins in the tissues of the body. Amyloid deposits are primarily made up of protein fibres known as amyloid fibrils. These amyloid fibrils are formed when normally soluble body proteins aggregate (clump together) and then remain in the tissues instead of safely going away. About 30 different proteins are known to form amyloid deposits in humans. These amyloid forming (‘amyloidogenic’) proteins are known as ‘precursor proteins’. Amyloid deposits cause disease by gradually accumulating within organs and thereby disrupting the structure and damaging the function of the affected tissues. Different types of amyloidosis are named according to the precursor proteins which form the amyloid fibrils. All have the initial ‘A’ denoting amyloidosis and letter(s) identifying the particular precursor protein which forms amyloid fibrils within the amyloid deposits. In ATTR amyloidosis, a blood protein called transthyretin (TTR) is the amyloid precursor protein that forms the amyloid deposits. ATTR amyloidosis can be either hereditary or acquired (nonhereditary, known as wild-type ATTR amyloidosis) Most of the treatment options available to patients have involved managing the symptoms and preventing progression of the disease.
But following strong interim results from the first six patients in a Phase 1 clinical trial of a geneediting treatment led by the UCL National Amyloidosis Centre at the Royal Free Hospital, London it is hoped this therapy will be a breakthrough for patients suffering from this debilitating condition. Patients on the trial receive, via a one-off infusion, a molecule known as CRISPR/Cas9, which inactivates the incorrect gene within the liver cells. With the gene no longer active in the liver, it is expected that the patient will only produce negligible levels of the harmful transthyretin protein. In the first six patients, the investigational therapy reduced production of the harmful protein by up to 96% by day 28 following treatment. There were no serious adverse events observed. The data were published today in the New England Journal of Medicine. As the trial progresses, patients will be given higher doses of the gene editing therapy with the hope that will drive the levels of toxic protein even lower.
CRISPR/Cas9, a Nobel Prizewinning technology, has been used in the past to edit cells outside the body. These are the first clinical data for an investigational therapy in which CRISPR/Cas9 is used as a medicine itself, infused intravenously to inactivate a target gene in a specific organ - in this case, the liver. Trial lead, Professor Julian Gillmore, of the UCL National Amyloidosis Centre, part of the UCL Centre for Amyloidosis and Acute Phase Proteins, said: “This is wonderful news for patients with this condition. If this trial continues to be successful, the treatment may permit patients who are diagnosed early in the course of the disease to lead completely normal lives without the need for ongoing therapy. “Until very recently, the majority of treatments we have been able to offer patients with this condition have had limited success. If this trial continues to go well, it will mean we can offer real hope and the prospect of meaningful clinical improvement to patients who suffer from this condition.”
SUSPECT ATTR-CM
(TRANSTHYRETIN AMYLOID CARDIOMYOPATHY)
A LIFE-THREATENING DISEASE THAT CAN GO UNDETECTED
Life-threatening, underrecognized, and underdiagnosed, ATTR-CM is a rare condition found in mostly older patients in which misfolded transthyretin proteins deposit in the heart.1-7 It is vital to recognize the diagnostic clues so you can identify this disease.
CONSIDER THE FOLLOWING CLINICAL CLUES, ESPECIALLY IN COMBINATION, TO RAISE SUSPICION FOR ATTR-CM AND THE NEED FOR FURTHER TESTING
HFpEF heart failure with preserved ejection fraction in patients typically over 60 years old5-7 INTOLERANCE to standard heart failure therapies (ACEi, ARBs, and beta blockers)8-10 DISCORDANCE between QRS voltage and left ventricular (LV) wall thickness11-13 DIAGNOSIS of carpal tunnel syndrome or lumbar spinal stenosis3,8,14-20 ECHO showing increased LV wall thickness6,13,16,21,22 NERVOUS SYSTEM —autonomic nervous system dysfunction-including gastrointestinal complaints or unexplained weight loss6,16,23,24
LEARN HOW TO RECOGNIZE THE CLUES OF ATTR-CM AT: S U S P E C T A N D D E T E C T . I E
References
1. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213. 2. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 3. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290. 4. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 5. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. 6. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 7. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. 8. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 10. Castaño A, Drach BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. 11. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. 12. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093. 13. Quarta CC, Solomon D, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849. 14. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614. 15. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. 16. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. 17. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17): 2040-2050. 18. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. 19. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207. 20. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011;42(9):1259-1264. 21. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. 22. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging. 2016;9(2):126-138. 23. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 24. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131.
Pinpointing How a Mutation causes Childhood Cancer
Researchers from Trinity have discovered how a specific genetic mutation (H3K27M) causes a devastating, incurable childhood cancer, known as diffuse midline glioma (DMG), and – in lab studies working with model cell types – successfully reversed its effects to slow cancer cell growth with a targeted drug. Their landmark work, supported by Worldwide Cancer Research and The Brain Tumour Charity, translates crucial new understanding of the genetics of DMG progression into a highly promising, targeted therapeutic approach and offers significant hope of improved treatments in the future.
The scientists now call for clinical trials to begin imminently, in which an already approved class of drugs called “EZH2 inhibitors” can be assessed. These drugs target the same key biological pathway involved in DMG as they do successfully in lymphomas and sarcomas — two cancers common in adults.
Adrian Bracken, Professor in Trinity’s School of Genetics and Microbiology, led the exciting research. He said, “We’ve taken a huge step forward in our study of DMG tumours and hope that the insights will help us design and implement precision oncologybased treatment approaches in DMG patients in the future. Crucially, ‘EZH2 inhibitor’ drugs have already received approval from the United States Food and Drug Administration for the treatment of two types of adult cancer. We propose these drugs could be impactful for children with DMG and, as a result, call for clinical trials to begin next. “Ultimately, we hope that our work – together with that of others focused in this area – will lead to curative clinical approaches for what is a truly terrible disease that can devastate families and for which there are currently no therapeutic options.”
Paediatric gliomas – harrowing, devastating cancers
Paediatric gliomas like DMG are among the most devastating of childhood cancers. Tumours typically arise in the brain and are very challenging to treat, with prognosis extremely poor. As such, effective therapeutic options are urgently needed. Dr Jane Pears, paediatric consultant oncologist at Our Lady’s Children’s Hospital, Crumlin, who treats children with this disease, said, “Despite combined best efforts, these tumours remain a devastating diagnosis for children and their families. The best treatment we can currently offer may extend survival for a few months but is not curative.
“We are now entering an exciting era of expansion of our knowledge of this disease at a molecular level, which in turn will lead us towards more targeted treatments. Thanks to collaborative translational efforts between scientists, such as Prof. Bracken and his team working in the laboratory, and doctors in the clinical setting, this will hopefully lead to the improved outcomes that we all so dearly wish to see.” Speaking to the importance of the work, Maeve Lowery, Professor of Translational Cancer Medicine at Trinity, and Academic Director of the Trinity St James’s Cancer Institute (TSJCI) said, “These findings have the potential to transform the treatment landscape of DMG tumours and improve outcomes for children with this challenging disease. Importantly, this pivotal work illustrates the
Adrian Bracken, Professor in Trinity’s School of Genetics and Microbiology
success of a precision oncology approach – where understanding how cancers develop on a genomic level can accelerate the development of more effective treatments with less side effects.
“The Precision Oncology Research Program at TSJCI, led by Prof Bracken, will build on this success to continue to develop new and innovative treatment strategies for adult and childhood cancers.”
Dr Becky Birch, Head of Research at The Brain Tumour Charity, which helped fund the study, said, “This is a really promising discovery that we hope will now pave the way for new and targeted treatments to be developed for children with diffuse midline gliomas (DMGs). With average survival still heartbreakingly short at less than 12 months, we urgently need to find new options to help slow the growth of this rare and often-inoperable cancer and give children diagnosed more time to live.
“It’s really exciting that we now better understand how a specific genetic mutation may be driving the disease, and even more so that drugs that may inhibit this process have already been tested in other cancers. If further research can now design EZH2 inhibitors to more effectively target DMG cells, we hope these drugs can be quickly advanced into clinical trials for children diagnosed with this devastating disease.”
