An Open Letter to the authors of ‘A Perspective on “cure” for Rett Syndrome.

Dear Professor Clarke and Dr Ana Abdala,

Like many parents of children or adults with Rett Syndrome, we at Reverse Rett read​ ​your recent piece​ in
Orphanet Journal of Rare Diseases with interest. As you know, our world is consumed by caring for our children
with Rett, and it is a world where hope is difficult to come by. We do not understand what positive contribution
your overwhelmingly negative and pessimistic article can bring to the Rett community.

Yes, life is difficult, yes the future is uncertain but yes, there is hope that the scientific efforts being put behind
Rett Syndrome will lead to treatments and even a cure in the coming months and years.

Particularly troubling is your false assertion that some Rett Syndrome organisations are ‘throwing money at’ and
concentrating on a cure instead of devoting resources to medical, or new ameliorative treatments. As Reverse
Rett is the only UK charity currently funding any Rett Syndrome research, we must assume this statement is
directed at us. For the record, for the last eight years, approximately 40% of our funding has focused on treating
symptoms, 40% has focused on developing cures and 20% on basic science. We do not throw money at
anything.

As anyone who even casually reads the scientific literature knows, there have been numerous scientific
advances in recent years which demonstrate that gene therapy and other ‘curative’ approaches can substantially
reverse symptoms and disability in young and older Rett mice. These scientific studies provide a rational basis
for hope that restoring MeCP2 protein will provide significant benefit - even in older children or adults with the
condition. At Reverse Rett we have a strong belief in the progress that science can make, and that is why we
focus on raising money to accelerate treatments and a cure for Rett Syndrome.

There are several recent publications demonstrating progress in the field which were not cited in your paper.
These include (and are not limited to):
● Developments in the safety and efficacy of gene therapy approaches for Rett syndrome (i) (ii)
● A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders [iii]
● Improvements in the accuracy and efficiency of RNA editing for ​MECP2​ (iv)

Aside from this progress in the literature, your paper also completely ignores​ ​the recent announcement​ that
biotech company AveXis is working with the FDA in the US to bring their Rett gene therapy program, AVXS 201
to human clinical trials in late 2018/early 2019.

The introduction of your paper states that ​‘scientists are all well aware that gene therapy and gene editing are in
their infancy​’ and that ‘​this is not such common knowledge among the families of those affected.’

You underestimate the degree to which families of people with Rett Syndrome are following medical
developments and understand that there are still many problems to solve.

The following positive developments in gene therapy which are now beginning to change the lives of people
affected by the relevant conditions, have been publicized by newspapers worldwide:
 ● Last year,​ ​the FDA approved ‘Luxturna’​ a gene therapy for blindness, the first to ever be approved by the
US regulatory authorities.
● In January 2018,​ ​NICE approved ‘Strimvelis,'​ a gene therapy for SCID, the first ever gene therapy to be
approved by the UK authority.
● Positive results have already been published by AveXis​ re their lead program, gene therapy for SMA type
1, (AVXS-101) and the product is now being manufactured in sufficient quantities to meet the need of
patients beyond clinical trials.

The section of your paper entitled ‘Challenges for gene therapy’ refers to the ‘Goldilocks principle,’ stating that
the amount of protein in each brain cell needs to be ‘just right’ in order to cure Rett Syndrome. It is correct that
too much MeCP2 is detrimental. However, the literature suggests that even low levels of MeCP2 in cells can be
significantly beneficial.

The paper goes on to read: ​‘We may have to accept that we can improve most of the severe symptoms but not
all.’

It does not take an expert to know that most families living with Rett Syndrome would likely find ‘improvement
of most but not all of the severe symptoms’ more than acceptable.

However, there is another element of this paper which raises concern.

Under the section entitled, 'Perils of a late cure,' there are repeated assertions that people with Rett Syndrome
may be ‘better off’ without curative approaches, implied by statements like ‘​the process of emerging from the
cocoon imposed by the disease might not be trouble-free​’ and ​‘these individuals might end up requiring life-long
pain management.’

Furthermore, your paper states that, ‘​the person with Rett undergoing gene therapy might still have underlying
psychiatric symptoms due to the sub-optimal levels of MECP2 in parts of their brain,​’ but does not mention that,
if this is true, these may be able to be addressed by existing psychiatric medications, nor is it clear whether the
person is likely to have suffered with this ‘underlying condition’ during their entire experience of Rett Syndrome.

Most worryingly, your paper states that ​‘such individuals may become more difficult to care for than before
treatment.’
Again, in these areas, the recent literature is not discussed. Research has questioned the historical view that
people with Rett Syndrome have profound cognitive disabilities. One study using eye gaze technology to assess
receptive language, showed that 32% of those tested were functioning at a level of mild cognitive impairment,
or even within the normal range of intelligence. Pain in Rett has now been studied at a physiological level and
historical and unsubstantiated assumptions about people with Rett having a higher pain tolerance have been
questioned:
● Assessing cognitive functioning in females with Rett syndrome by eye-tracking methodology [v]
● Cognitive function in Rett syndrome: Profoundly impaired or near normal? [vi]
● Detecting autonomic response to pain in Rett syndrome [vii]

In the last 2-3 years Reverse Rett has been working to help facilitate the implementation of the first ever UK
clinical trial for a potential treatment for Rett Syndrome.
Reverse Rett continues to work in partnership with both Newron and the trial site at King’s College Hospital to
support the trial in the following ways:
● Identifying patients from the UK Rett Syndrome Patient Registry at Reverse Rett
● Providing ongoing funding a dedicated Clinical Trial Coordinator at the trial site at King’s College Hospital
(now in its second year)
● Pre-screening patients and referring to trial site where appropriate
● Assisting families with their travel and accommodation arrangements on behalf of Newron, the
pharmaceutical company sponsoring the trial

This work is being done by Reverse Rett to help support the development of Sarizotan as a ​treatment for one
symptom​ of Rett Syndrome, not for a cure. Additionally, Reverse Rett is an active member of the UK Rett
Disorders Alliance, which is working with other Rett patient groups to try to spread best-practice clinical
practices for all patients in the UK.

For the record, Reverse Rett is an organisation founded and run by parents of older children and adults with Rett
Syndrome. To state that choosing to support a research-focused or family support organization is likely to relate
to the age/stage of the affected individual and the family’s pattern of adjustment is not only patronizing and
divisive, it is also factually incorrect.

Families of adults with Rett regularly give their support to Reverse Rett and families of adult women and men
with Rett Syndrome add the person they love to the UK Rett Syndrome Patient Registry at Reverse Rett every
day.

We don’t need your permission, you see, to be hopeful.

Hope doesn’t come on prescription. We can have it every day, whenever we like.

For most of us it comes and goes. For those who read, it is grounded in science and in publications like those
cited above.

From our perspective, for now, there’s just no reason to be anything other than optimistic.

Reverse Rett

‘Optimism is the faith that leads to achievement. Nothing can be

done without hope and confidence.’ ​-Helen Keller
Footnotes:
(i) Gadalla KKE, Vudhironarit T, Hector RD, Sinnett S, Bahey NG, Bailey MES, et al. Development of a Novel AAV
Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome.
Molecular therapy Methods & clinical development. 2017;5:180-90. doi: 10.1016/j.omtm.2017.04.007. PubMed
PMID: 28497075; PubMed Central PMCID: PMCPMC5423329​ ​View article

(ii) Tillotson R, Selfridge J, Koerner MV, Gadalla KKE, Guy J, De Sousa D, et al. Radically truncated MeCP2 rescues
Rett syndrome-like neurological defects. Nature. 2017;550(7676):398-401. doi: 10.1038/nature24058. PubMed
PMID: 29019980.​ ​View article

[iii] Lieselot L. G. Carrette, Chen-Yu Wang, Chunyao Wei, William Press, Weiyuan Ma, Raymond J. Kelleher,
Jeannie T. Lee. A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked
disorders. Proceedings of the National Academy of Sciences, 2017; 201715124 DOI: 10.1073/pnas.1715124115
View article

(iv) Sinnamon JR, Kim SY, Corson GM, Song Z, Nakai H, Adelman JP, et al. Site-directed RNA repair of endogenous
Mecp2 RNA in neurons. Proceedings of the National Academy of Sciences of the United States of America.
2017;114(44):E9395-E402. doi: 10.1073/pnas.1715320114. PubMed PMID: 29078406​ ​View article

(v) J. Ahonniska-Assa, O. Polack, E. Saraf, J. Wine, T. Silberg, A. Nissenkorn, B. Ben-Zeev Assessing cognitive
functioning in females with Rett syndrome by eye-tracking methodology Eur J Paediatr Neurol, 22 (2018), pp.
39-45​ ​View article

(vi) Loffler G, Gordon GE. Cognitive function in Rett syndrome: Profoundly impaired or near normal? Eur J
Paediatr Neurol. 2018 Jan;22(1):2-3. doi: 10.1016/j.ejpn.2017.12.006. Epub 2017 Dec 21​ ​View article

(vii) O'Leary HM, Marschik PB, Khwaja OS, Ho E, Barnes KV, Clarkson TW, Bruck NM, Kaufmann WE. Detecting
autonomic response to pain in Rett syndrome. Dev Neurorehabil. 2017 Feb;20(2):108-114. doi:
10.3109/17518423.2015.1087437. Epub 2015 Oct 12.​ ​View article