Reproductive options for patients with mitochondrial DNA disease: using mitochondrial donation to prevent disease transmission

Transcription

1 Reproductive options for patients with mitochondrial DNA disease: using mitochondrial donation to prevent disease transmission Emma Watson Newcastle NHS Highly Specialised Service for Rare Mitochondrial Disorders, Wellcome Centre Mitochondrial Research, Newcastle University, UK

2 Mitochondrial Disease Mitochondrial disease is a complex disease that can affect any tissue at any age

3 Mitochondrial DNA Pathogenic Variants DiMauro et al. Nature Rev. Neurol

4 Mitochondrial DNA Genetic Rules Maternal inheritance Heteroplasmy, homoplasmy and variable penetrance Homoplasmy Heteroplasmy Threshold effect Mitotic segregation

5 Mitochondrial Disease Estimated to be 6500 females in the UK affected or at risk of mtdna disease Currently no effective treatments for mtdna disease Reproductive options Counselling Ovum donation Prenatal diagnosis Pre-implantation genetic diagnosis Mitochondrial donation

6 Prenatal Testing and Pre-Implantation Genetic Testing : 62 CVS (42 nuclear gene testing, 20 mtdna) 12 PGD mtdna pathogenic variant Level of mutation in individual blastomeres (%) Mutation range in additional samples (%) Level of mutation in mother (%) Successful pregnancy m.3243a>g MTTL1 0, 8-15 blood, 39 urine N m.3243a>g MTTL1 1, 2, 2, 6,13-15 blood, 39 urine N m.3243a>g MTTL1 1, 52, 62, 69, 69, and blood, 76 urine N m.3243a>g MTTL1 1, 12, 31, 38, 64, blood, 76 urine N m.3688g>a MTND1 2, 2, 4, 5, 8, blood, 50 urine Y m.8344a>g MTTK 65, 74 32, 50, 54, 60, 61, 61, 62, 62, 63, 73, 74, 76, 76 m.8344a>g MTTK 70, 75, 93 32, 33, 35, 43, 57, 57, 58, blood, 76 buccal 79 urine 56 blood, 66 buccal 67 urine m.8344a>g MTTK 48, 48, 67, 79, 98 46, 72, blood, 70 urine N m.8993t>c MTATP6 98, 99, 99, blood N N? m.10158t>c MTND3 0, 0, 7, 18-5 blood, 33 urine 16 buccal m.10158t>c MTND3 1, 1, 1, 10-5 blood, 33 urine 16 buccal N Y m.10197g>a MTND blood, 11 buccal 14 urine N

7 Homoplasmic mtdna Mutations and Variable Penetrance Homoplasmic trna mutations m.1624c>t MTTV LHON mutations Leber s Hereditary Optic Neuropathy (LHON) symptoms usually begin as sudden, painless loss of central vision. The classic pattern is for one eye to suddenly lose central vision, then on average 8 weeks later the other eye also loses central vision, though many variations on this pattern are possible. After this acute phase, severe visual loss in both eye remains. Reading, driving and recognizing faces are impossible.

8 Mitochondrial Disease Estimated to be 6500 females in the UK affected or at risk of mtdna disease Currently no effective treatments for mtdna disease Reproductive options Counselling Ovum donation Prenatal diagnosis Pre-implantation genetic diagnosis Mitochondrial donation

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10 The Pathway to Mitochondrial Donation 2001/2002: The use of nuclear transfer techniques for research with early human embryos was permitted in amendments made to the original Human Fertilisation and Embryology Act (1990). 2005: An HFEA research license to explore the use of nuclear transfer techniques to avoid diseases due to abnormal mtdna was granted to the Newcastle Team. 2008: Revision of HFE Act included a specific provision to allow for regulations to be passed by Parliament to permit the clinical application of techniques that alter the DNA of an egg or embryo to prevent the transmission of serious mitochondrial disease. 2011: HFEA to scope expert views on the effectiveness and safety of mitochondrial transfer. No evidence to suggest that the technique of mitochondrial donation was unsafe for clinical use

11 on balance we believe that if these novel techniques are adequately proven to be acceptably safe and effective as treatments, it would be ethical for families to use them

12 The Pathway to Mitochondrial Donation cont. 2013: Following collective outcomes of the scientific reviews, the public consultation and the report of the Nuffield Council on Bioethics, the UK Government announces their decision to publish draft regulations to amend the 1990 Act to permit the clinical application of mitochondrial donation. December 2014: Draft regulations were laid before parliament House of Commons voted by 382 to 128 in support House of Lords voted by 280 to 48 in support

13 Success! Jane Ellison MP Parliamentary Under Secretary of State for Public Health 5pm 4 th March 2015 HFEA statement on mitochondrial donation

14 Mitochondrial Donation: Patient Engagement Patient support to effect change through press and media Patients meeting their MP s

15 Mitochondrial Donation Preventing the transmission of mtdna disease Metaphase II spindle transfer (MST) Pronuclear transfer (PNT)

16 >150 families/year in the UK; >750 families/year in the US Gorman et al. New Engl. J. Med 2015

17 Reproductive Options Patient Pathway REPRODUCTIVE OPTIONS CLINIC: Counselling Expert IVF Clinician input Expert Mito Clinician input Decision-making Pre-pregnancy advice Mitochondrial Donation Preimplantation Genetic Diagnosis Egg Donation IVF pathway Oocyte vitrification Egg Donor pathway Mitochondrial Donation Procedure

18 Reproductive Options Donor Pathway Donor referral or contact Bring your own donor! Donor assessment IVF mtdna sequencing Donor assessment for mitochondrial disorders IVF clinical pathway Fresh oocytes for mitochondrial donation

19 Mitochondrial Donation: Pregnancy Care Pathway Inform and liaise with local obstetric team regarding high risk pregnancy CVS referred to laboratory for testing Liaise and support mothers throughout pregnancy Support through labour and delivery

20 Paediatric Care Pathway following Mitochondrial Donation hours neonatal check 1-28 days new born hearing test STANDARD NHS CARE 5-8 days neonatal blood spot 6-8 weeks physical examination general review health visitor Blood, urine and buccal for mtdna analysis Access to mitochondrial clinic and specialist paediatric advice 18 Month mitochondrial paediatric review Blood, urine and buccal for mtdna analysis STANDARD NHS CARE 30 Months general review 4-5 Years mitochondrial paediatric review Blood, urine and buccal for mtdna analysis

21 Where we are now and the future. Accepting NHS referrals for mitochondrial donation via the reproductive options pathway First applications have been submitted to the HFEA for consideration Considerable overseas interest NHS service needs to be established and shown to be successful Further information and guidance is available, please contact us!

22 Thank you To all our mitochondrial patients and their families Newcastle Fertility