RETT SYNDROME RESEARCH TRUST2011 ANNUAL REPORT

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LETTER FROM THE EXECUTIVE DIRECTORDear Supporters,

On October 20, 1998, my two-year old daughter, Chelsea, was officially diagnosed with Rett Syndrome. At that mo-ment I made her a promise: I would do everything in my power to free her from Rett Syndrome.

In pursuit of that promise, I co-founded two organizations: first the Rett Syndrome Research Foundation in 1999(later merged with IRSA to become IRSF) and more recently the Rett Syndrome Research Trust. Through my workI have supervised peer-review for almost a thousand research applications, organized numerous scientific sympo-siums and think tanks, heard countless science talks and spoken to more scientists than I ever imagined possible.

My work with RSRT is ambitious and often difficult, especially when also dealing with the never-ending challenges ofraising a child with complex medical needs. However, working with like-minded trustees, organizers of events both bigand small, and the founders of organizations who support our efforts has been a supremely rewarding experience.Their drive to maximize research funds in a no-nonsense, get-the-job-done fashion has been inspiring and energizing.

RSRT had a remarkable year. Our young organization, with the tireless work of our trustees, motivated volunteersand contributors and no staff, beyond myself, moved Rett research forward in 2011:

• RSRT committed $3.6 million to new research in 2011. This is a record amount for any Rett advocacy group in agiven year.

• A $1 million gift created the MECP2 Consortium.

• Despite difficult economic times, we saw a 60% increase in donations.

• RSRT launched a pro bono 3-month awareness campaign in Times Square seen by millions throughout the holidayseason, including New Year’s Eve.

• 96% of our donations funded our research program.

I feel, for the first time since that bleak day in 1998, that the efforts of the sci-entists and the donors who support them may begin to bear fruit. However,much work remains to be done, both scientifically and financially. The researchthat lies ahead needs to be exponentially expanded.

As I bend down to lay my 15-year-old daughter gently into her bed each night,we often stare intently into each other's eyes. As her gaze bores into me, I feelher holding me to my promise. I invariably ask myself "Did I do right by hertoday?" It is with serious and deep purpose that I renew my obligation to herand to each person with Rett Syndrome. This sense of responsibility extendsalso to our supporters and volunteers who donate money, time, and energy.Their confidence in our work reinforces our collective strength and will to defeatRett Syndrome.

If you know a family affected by Rett Syndrome, please consider making 2012the year you become more involved with our efforts.

If you are the parent of a child with Rett, perhaps you've made a similar promiseto your daughter. Help us to fulfill your promise ... and mine.

Monica Coenraads

To everyone who supportedus in 2011 please know

your donation has made a difference. Your generosity

is deeply appreciated.

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WHAT IS RETT SYNDROME?

Imagine the

symptoms of

autism,

cerebral palsy,

Parkinson’s,

epilepsy, and

anxiety disorders…

all in one little girl.

Rett Syndrome is a severe neurological disorder that is diagnosed almost exclu-sively in girls. It strikes at random in early childhood, causing seemingly healthylittle girls to lose the ability to speak and control their movements. A child withclassic Rett is in a wheelchair, unable to speak or use her hands. She suffersfrom disordered breathing, severe digestive problems, orthopedic abnormalities,seizures and extreme anxiety. It is the most physically disabling of the autisticspectrum disorders.

Learning that their daughter has Rett Syndrome is a devastating experiencefor parents. It means reassessing everything they had expected for their family,accepting the loss of hopes and dreams, and coping with feelings of fear andisolation. It also means adjusting to a new way of life, one that’s filled with med-ical appointments, non-stop therapies, equipment, special education, insurancewoes, and ceaseless advocacy on their daughter’s behalf.

There is currently no significant treatment. Each symptom is treated individually,often with limited success. Some girls die in childhood, but many survive intoadulthood, requiring total, 24-hour-a-day care.

Rett Syndrome is caused by mutations in a gene called MECP2. This geneproduces a multi-functional protein, also called MeCP2, which is required tomaintain normal brain function.

While Rett Syndrome causes severe physical and communication difficulties,studies have shown that girls’ brains remain undamaged. Though it was onceseen as a degenerative disease, we now know that restoring adequate levelsof MeCP2 protein can dramatically reverse symptoms.

Girls with Rett Syndrome know and understand much more than their bodiesallow them to show. Breakthroughs in research have the potential to ‘unlock’these girls, and restore them to health.

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CREATION OF THE RETT SYNDROME RESEARCH TRUST

A cure for Rett SyndromeIt’s our obsession

There is only one road to treatments and a cure for Rett Syn-drome, and it is research. How intensively this research is pur-sued depends, in large part, on available financial resources.

The genetic cause of the disorder was identified in 1999 by HudaZoghbi, M.D. Almost immediately a small, determined group ofparents, led by Monica Coenraads, established the Rett Syn-drome Research Foundation to leverage this breakthrough dis-covery and to accelerate and intensify research efforts. In 2007,another landmark discovery took place. Adrian Bird, Ph.D., un-expectedly and dramatically reversed the symptoms of Rett Syn-drome in late-stage mice models of the disease.

And once again, a small group of experienced, research-ori-ented parents took a hard look, assessed priorities and swiftlycreated an agile, streamlined, highly efficient nonprofit devotedexclusively to science: the Rett Syndrome Research Trust. Ourmission is to reverse Rett Syndrome, not in mice, but in people.

The symptoms of Rett Syndrome are relentless. Our work isequally relentless. The hope we instill in parents isn’t “feelgood” optimism to help us cope with a difficult diagnosis. It isoptimism that is founded on high-impact science and the veryreal possibilities that lie ahead.

“Monica Coenraads’

spectacular success is based

on relentless and informed

networking in research circles

plus a single-minded focus

on the ultimate goal – a cure

for Rett Syndrome. She has

inspired scientists to

appreciate that goal

and share it.”

Professor Adrian BirdUniversity of Edinburgh

RSRT Trustee and Scientific Advisor

KEY FACTSLaunched: September 2008

Funds committed: $8 million% of funds spent on research: 96%

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OUR APPROACH TO RESEARCH

We do not shy away from high- risk projects; thesemay prove to be the experiments that move the field

forward by leaps rather than incremental steps.

Rett Syndrome: The only way to defeat it is to outsmart itRett Syndrome Research Trust is an organization that is focused on science and founded on love. It is rootedin a deep knowledge of both the science and the realities of living with Rett Syndrome. It is committed to inno-vation, intellectual rigor and “seizing the moment”.

We do not shy away from high-risk projects; these may prove to be the experiments that move the field forwardby leaps rather than incremental steps. Beyond financial support to scientists, we also provide access to intel-lectual capital. Our well-established, global scientific networks provide both seasoned Rett researchers andnewcomers with connections and input to advance their work.

We convene conferences around specific sets of questions. These meetings are invitation-only and are de-signed to encourage free exchange of information about ongoing research, including unpublished work. Theintimacy of this format has been quite successful in generating ideas for new research directions and collabo-rative efforts.

We support research, in parallel, in four categories:

1. Understanding the function of the MeCP2 protein: Unlike most other autism spectrum disorders, we knowthe root cause of this disorder, but explaining in molecular terms just why absence of functional MeCP2 bringsabout Rett’s particular constellation of symptoms still eludes us. It stands to reason that understanding thefunction of the protein will be vital for designing rational treatment therapies.

2. Increasing levels of MeCP2: Since Rett Syndrome is caused by a deficiency of MeCP2 protein, one ap-proach to curing the disorder, therefore, is to restore normal levels. This could be accomplished in a numberof ways including small molecule therapeutics (drugs) and/or biologics (gene therapy, protein replacement).

3. Modifier Genes: It is likely that differences in the genetic make-up of an individual modulate the impact ofan MECP2 mutation. There are individuals who have common MECP2 mutations and normal X chromosomeinactivation, yet do not have Rett Syndrome. It is likely that these individuals are protected from their MECP2mutation due to modifying mutation(s) in other genes. Identifying such modifier genes could open new avenuesfor treatment.

4. Alleviation of Specific Symptoms: The array of individual symptoms in Rett Syndrome is so significantthat eliminating a single one may, in many cases, dramatically improve quality of life. Finding an FDA approveddrug/compound or procedure to ameliorate a symptom (such as disordered breathing, extreme anxiety,seizures) can be the quickest and most cost effective route to clinical trial.

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RESEARCH GRANTS TOTALING $3.6 MILLION AWARDED IN 2011

Donors: This is your money at work!• MECP2 ConsortiumAdrian Bird, Ph.D. – University of EdinburghMichael Greenberg, Ph.D. – Harvard UniversityGail Mandel, Ph.D. – Vollum Institute (OHSU), Howard Hughes Medical Institute

• Investigating novel therapeutic approaches for Rett SyndromeHuda Zoghbi, M.D. – Baylor College of Medicine, Howard Hughes Medical Institute

• Immune modulation as a new therapeutic approach for Rett SyndromeJonathan Kipnis, Ph.D. - University of Virginia

• A High-Throughput Screen to identify compounds that reactivate the functional MECP2allele in Rett SyndromeJeannie Lee, M.D., Ph.D. – Harvard University

• Identification of gene modifiers that ameliorate Rett symptomsMonica Justice, Ph.D. - Baylor College of Medicine

• mGluR5 Signaling – Is it Implicated in Rett?Mark Bear, Ph.D. - MIT

• Effect of the serotonin 1a agonist F15599 on respiration and locomotion in a mouse modelof Rett syndromeJohn M Bissonnette, M.D. - Oregon Health and Science University

• Vitamin D therapy for MeCP2 target Irak1/NF-kB dysregulationJeffrey Macklis, M.D., D.HST - Harvard University

• Tri-State Rett Syndrome CenterAleksandra Djukic, M.D., Ph.D. - Albert Einstein College of Medicine / Montefiore Children’s Hospital

A full list of research projects funded by RSRT is included at the end of this report.

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OUR ALLIANCES

Launched in 2010, RSRT UK shares our common name and our common mission.2011 was a stellar year for RSRT UK, who were able to contribute $500K to ourresearch program.

Founded by Shmulik and Lilit Zysman, the Rett Syndrome Research and TreatmentFoundation has partnered with RSRT from day one. To date, they have contributeda total of $1.4 million in support of RSRT’s research program. Their activism anddedication have been essential to our endeavors.

RSRT UK Reverse Rett LondonRSRT UK Trustees: RitaRoss, Rachael Bloom,and Andy Stevenon

Shmulik Zysman andhis daughter Hadar

Rett Syndrome Research and Treatment Foundation Gala

Kate Foundation Gala

“There is no such thing

as local science, there is

no such thing as national

science, there is only

global science.”

Professor Adrian Bird

The ability of RSRT to supporthigh-level science is greatly en-hanced by our alliances with like-minded national and internationalRett organizations. We are hon-ored by the commitment andgrateful for the support of the fol-lowing groups, who contributed atotal of $1.3 million to our re-search programs in 2011.

• RSRT UK• Rett Syndrome Research and

Treatment Foundation (Israel)• Kate Foundation for Rett

Syndrome Research• Skye Wellesley Foundation • Girl Power 2 Cure• Rocky Mountain Rett

Association• Rett Syndrom (Germany)• Stichting Rett Syndroom

Founded by Sarah and Jeff Canavan, the Kate Foundation for Rett Syndrome Research genererated proceeds of $200k to RSRT.

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OUR ALLIANCES

Various Girl Power 2 Cure events such as “Gardenof Hope” & “Golf for a Cure” raised proceeds of

$100K for RSRT.

Launched in late 2010 by Claudia Petzold, we welcome the support of this German organization

and the $50K contributed in 2011.

Rocky Mountain Rett Syndrome Association Walkathon

The RMRA generated $75K for RSRT.

Supporters of the Skye Wellesley Foundationgenerated $125K for RSRT.

We are grateful toSuzanne Middelink andher supporters for the

$10K donation.

Emma & Skye Wellesley ChristopherWellesley

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MECP2 CONSORTIUM

A New Way of Doing Business

“Our joint view is that solving thistricky problem calls for cooperationbetween laboratories with differentexpertise. To be honest, I find it re-freshing to be part of an endeavorthat transcends our personal ambi-tions for a higher purpose.”

Professor Bird

The goal of the Consortium, from mypoint of view, is to put our heads to-gether to generate new ideas, and tocritically evaluate each other’s ideasand experiments, and to collaborateon experiments where the expertiseis complimentary.”

Professor Mandel

“The goal of the Consortium is togain rapid understanding of the molecular and cellular basis of RettSyndrome through a collaborative ef-fort. I feel that although the Consor-tium research effort began recently,we are already seeing a benefit. Thepace of progress in understandingRett Syndrome is already beginningto accelerate.”

Professor Greenberg

Kathy and Tony Schoener

In 2011, RSRT launched the MECP2Consortium, a dynamic collaboration be-tween the laboratories of three distin-guished scientists: Adrian Bird of theUniversity of Edinburgh, Michael Green-berg of Harvard University and Gail Man-del of Oregon Health & SciencesUniversity. Made possible by a $1 milliongift by RSRT Trustee Tony Schoener andhis wife Kathy, the Consortium wasformed to definitively determine how thecomplex “Rett protein,” MeCP2, func-tions and exerts its powerful influence onthe human brain. The Consortium is athree-year project with a budget of $1.8million.

Through monthly teleconferencing, semi-annual meetings and informal, ongoingcommunication, the Consortium acceler-ates progress through synergistic inter-action between the three PrincipalInvestigators and the members of theirlaboratories.

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THE CHARLES T. BAUER FOUNDATION LAUNCHES HARVARD PROJECT

CREATION OF THE MECP2 DUPLICATION SYNDROME FUND AT RSRT

Common Gene – Common Goal

Just in time for the holidays, RSRT received a gracious $300,000 gift from TheCharles T. Bauer Foundation to support a project spearheaded by Jeannie Lee,Ph.D. at Harvard University. Dr. Lee will undertake a state-of-the-art screen toidentify compounds that can reactivate the silent MECP2 gene on the inactiveX chromosome. Simply put, successful activation of the gene could mean acure for Rett Syndrome.

Through his friendship with Susan Knott, whose grandchild Ruby has Rett Syn-drome, Charles T. Bauer Foundation trustee, Ted Bauer, learned of Rett Syn-

drome and RSRT’s need forfunding to pursue the screeningproject.

We are deeply grateful to TheCharles T. Bauer Foundation fortheir extraordinary gift and theircommitment to Rett Syndrome re-search.

Unlike Rett Syndrome, which is caused by mutations or dele-tions in the MECP2 gene, the symptoms of the Duplication Syn-drome arise when an area of the X chromosome (Xq28), whichincludes the MECP2 gene, is erroneously duplicated. The pre-cise duplication section may vary from one individual to another,possibly determining the severity of the disease.

The MECP2 Duplication Syndrome has so far been diagnosedin both male and females and may be quite prevalent. Prelimi-nary studies suggest that 1% of cases of X-linked intellectualimpairment might be due to this syndrome. Core phenotypes inboys include infantile hypotonia, mild dysmorphic features, de-velopmental delay, absent to minimal speech, recurrent infec-tions, progressive spasticity especially of the lower limbs, ataxia,autistic features, and seizures. Females with MECP2 duplicationwithout X chromosome inactivation skewing have been reportedand present similarly to boys.

Deciding to take full advantage of RSRT’s knowledgeable operating base and well-established scientific net-works, affected families have created the MECP2 Duplication Syndrome Fund at RSRT for the exclusive sup-port of scientific meetings and projects devoted to the study and means of treatment.

Above: Ruby RandolRight: Ted Bauer,

Susan Knott, Jesse and Jeremy Randol

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EVENTS

Co-ChairsHeidi Epstein &

Marci Valner

Hope for Hannah & Gaby Gala Oct. 20th - $525K

Reverse Rett NYNov. 9th - $370K

Dr. Sasha Djukic &Co-Chairs Rachel &Jason Rothschild

Aimee, Al and Eva Fini

Boston Reverse RettSept.14th - $90K

“Hope has two beautiful

daughters. Their names

are anger and courage;

anger at the way things

are, and courage to see

that they do not remain

the way they are."

St. Augustine

“Your child has Rett Syndrome.”The implications of these wordssend shockwaves of sorrow andfear through parents’ souls.There is no single “right” way torespond to the diagnosis or to getthrough a day, a week, a yearwith Rett Syndrome. And yet, formany of us, the love and protec-tive instincts toward our childrenbecome stronger and fiercer.

Whether it is anger or optimismor the conviction that science willprevail, the families whofundraise for RSRT and their net-work of relatives, friends and col-leagues who support them areinspiring and resourceful – theyhave our respect and our grati-tude. Simply put, they make ourwork possible.

EVAning of HopeJuly 16th - $150K

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EVENTS

Donations can be sent via check to:

RSRT67 Under Cliff RoadTrumbull, CT 06611

via credit cardwww.rsrt.org

To support an existingevent or to start your ownevent please contact us

events@rsrt.org

For all other inquiriesplease contactinfo@rsrt.org

Mace Walker and supporters at Race for MaceJune 11th - $12K

Quest for a Cure WalkathonOct. 9th - $33K

Elizabeth and Dennis Jones and family at Jocelyn’s JourneySeptember 24 - $50K

Robert, Annie & Mikyla Smith Cruise 2 Cure - June 17th - $56K

RETT: The Documentary RSRT on The View

Despite the fact that Rett is the leadinggenetic cause of severe impairment infemales, awareness of the disorder isminimal in the public at large.

RSRT launched a pro bono three-month public service announcement (PSA) starting November 1st in themost iconic of all advertising venues – Times Square in New York City. The PSA ran an average of nine timesan hour on the colossal 6,000 square foot Mediamesh display at the corner of 42nd Street and 8th Avenue. Anestimated 1.5 million people viewed the PSA daily. The message of hope for a cure for Rett ran throughout theholiday season including the Macy’s Thanksgiving Parade and New Year’s Eve.

We are grateful to everyone who donated their time and effort to make this happen: Bill Koenigsberg, CEO andFounder of Horizon Media; Garage Media; A2AMedia; and Jon Denny, film and TV producer, for creating our PSA.

In 2009, filmmakerJason Rem of REMEntertainment at-tended an elegantcharity event, Hopefor Hannah, organ-ized in Los Angelesby RSRT TrusteeHeidi Epstein andher husband, Jon-athan. That evening,Rem was exposedfor the first time toimages of the heart-breaking devastationcaused by Rett Syn-drome, a childhoodneurological disor-der he had neverheard of before.

Rem decided to explore creating a short five-minutefilm to increase awareness and help the cause. In-trigued by both the disease and the research, Rempersuaded industry friends to donate their time and ef-fort. His camera captures the constant stress, as wellas the love and devotion the disorder elicits from fam-ilies and the determination exhibited from scientists.The film, available for purchase on the RSRT web-

site, is now being entered into film festivals. Proceedsfrom the sales benefit RSRT’s research program.

Rett Syndrome received national TV media atten-tion on January 28th when the co-hosts of The Viewinterviewed Manny and Stefanie Gutierrez abouttheir daughter Anna and their journey with Rett Syn-drome, and Monica Coenraads, Executive Directorof RSRT.

The audience received a complimentary copy of thedocumentary, RETT. We are grateful to Manny andStefanie for sharing their story and indebted to thehosts and executives of The View for raising aware-ness of Rett.

Times Square PSA

RAISING AWARENESS THAT RETT IS REVERSIBLE

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PROJECTS SUPPORTED BY RSRT – TOTAL COMMITMENT $8 MILLION

MECP2 Consortium

Increasing Levels of the MeCP2 Protein

Adrian Bird, Ph.D., Michael Greenberg, Ph.D., Gail Mandel, Ph.D.

Made possible by a $1 million gift by RSRT Trustee Tony Schoener andhis wife Kathy, the Consortium is a dynamic collaboration formed to de-finitively determine how the complex protein, MeCP2, functions. Deepknowledge of its structure and roles in neurological development andmaintenance will inform the design of rational treatments for Rett andrelated disorders.

Identification of drugs or genes that activate the silent MECP2 geneAntonio Bedalov, M.D., Ph.D., Fred Hutchinson Cancer Research CenterThe gene that is mutated in Rett Syndrome, MECP2, is located on the X chromosome. All females have two X chro-mosomes in every cell but only one is inactivated. The goal of this project is to identify drugs/compounds and/orgenes that will activate the silent MECP2 on the inactive X chromosome.

A High-Throughput Screen to identify compounds that reactivate the functional MECP2 allele in RettSyndromeJeannie Lee, M.D., Ph.D., Harvard UniversityDr. Lee will develop an assay using mouse cells that can detect activation of the MECP2 gene. Utilizing the significantresources of The Broad Institute, the assay will undergo a high-throughput screen to identify compounds able toturn on expression of the gene.

High-throughput small molecule screen to activate the silenced Mecp2 allele using Mecp2-GFP miceBen Philpot, Ph.D., Bryan Roth, Ph.D., Mark Zylka, Ph.D., University of North Carolina at Chapel HillThese investigators have successfully employed a high-throughput screen to identify compounds that unsilence the genefor Angelman Syndrome, UBE3A. This project is a pilot study to investigate the use of a fluorescence-based screen (usingMeCP2-GFP mice created by Adrian Bird) to identify compounds to unsilence MECP2 on the inactive X chromosome.

Identification of the mechanisms that silence the MECP2 gene on the inactive X chromosomeMarisa Bartolomei, Ph.D., University of PennsylvaniaA synergistic project to the ones described above this effort is also focused on activating the silent MECP2 gene on theinactive X. Dr. Bartolomei seeks to identify the molecular mechanisms that keep MECP2 silent in the hopes that thesemodifications can be reversed with drug(s). It is possible that activating the silent MECP2 may require a combination of

loosening up the mechanisms that keep this gene silent in concert with activation drugs iden-tified in the above project.

Evaluate the outcome of boosting MeCP2 levels in wildtype cells of female miceHuda Zoghbi, M.D., Baylor College of MedicineFemales with Rett Syndrome lack functional MeCP2 in approximately 50% of their neu-rons while 50% have normal (wildtype) MeCP2. Dr. Zoghbi will explore whether boostingMeCP2 levels in the wildtype cells might enhance the overall neural network activity evenin the face of the 50% null cells. Encouraging results could set the foundation for a largescale screen to identify targets that can modulate MeCP2 levels. This knowledge will becritical for Rett Syndrome as well as the MECP2 Duplication Syndrome.

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OUR PROJECTS

Alleviation of Specific Symptoms

A search for molecular chaperones for MeCP2 (T158M)Adrian Bird, Ph.D., University of EdinburghPrevious work from the Bird lab suggests that the T158M mutation (the most common mutation) disrupts thenatural folding that occurs at this particular amino acid position in the MeCP2 protein. This project seeks toidentify small molecules that can counteract the misfolding induced by the MeCP2-T158M mutation. The hopeis that restoring proper folding will improve the symptoms of the disorder.

AAV9 Gene Therapy for RTTBrian Kaspar, Ph.D., Gail Mandel, Ph.D., Ohio State University, Oregon Health Science UniversitySince Rett Syndrome is a single gene disorder, gene therapy is potentially a viable approach to treatment. Re-cently the Kaspar lab has reported that Adeno-Associated Virus, serotype 9 (scAAV9), is able to cross the blood-brain-barrier achieving global distribution in the central nervous system when administered via the bloodstream.This collaborative project between Kaspar, a leading gene therapist, and Gail Mandel, a prominent Rett researcher,will determine the clinical potential of scAAV9 in gene replacement strategies for Rett Syndrome. The Kaspar labhas already been successful in initial trials of SMN gene delivery with scAAV9 for treating a mouse model ofSpinal Muscular Atrophy (SMA), completely rescuing the lethal phenotype seen in that disease model. The ge-netics of the Rett model are ideally suited to investigation of the clinical utility of scAAV9.

Adeno-associated Virus-mediated Gene Transfer for the Treatment of Rett SyndromeRonald C. Crystal, M.D., Adrian Bird, Ph.D., Weill Cornell Medical College, University of EdinburghThis project also seeks to develop a gene therapy approach to the treatment of Rett but with a different vector thanthe project outlined above. The vector used will be the new generation AAVrh10 which has shown remarkable geneexpression throughout the central nervous system. The Crystal lab is one of only a few in the world that has con-ducted gene therapy clinical trials in humans. Complimenting the Crystal expertise at gene therapy and clinical trialsis Adrian Bird, who brings his deep knowledge of MeCP2 and the Rett animal models. If gene therapy with AAVrh10is successful in the mice, Crystal’s past experience in clinical trial development will prove invaluable.

Evaluate the outcome of deep brain stimulation (DBS) on cognition in Rett mouse modelsHuda Zoghbi, M.D., Baylor College of MedicineThe use of DBS has revolutionized the treatment of Parkinson’s and is now also used for depression, OCD,Alzheimer’s and more recently in pediatric disorders such as dystonia and Tourette. The availability of Rett mousemodels allows us the opportunity to explore potential benefits of this procedure for Rett. Encouraging data can bequickly moved to the clinic.

Immune modulation as a new therapeutic approach for Rett SyndromeJonathan Kipnis, Ph.D., University of VirginiaRecent data generated in the Kipnis lab demonstrates that immune systemand T cells, in particular, are required for normal brain function. T cells, workingthrough soluble factors (cytokines), control synaptogenesis, regulate adult neu-rogenesis, and affect levels of brain derived neurotrophic factor (BDNF). De-pletion or malfunction of T cells correlates with reduced synaptogenesis,decreased levels of BDNF, and impaired brain function. Rett syndrome is as-sociated with motor malfunction, reduced neurogenesis, and deficit in BDNF.Studies indicate that some aspects of T cell function are impaired in Rett pa-tients. Therefore, Kipnis hypothesizes that a malfunction in adaptive immunesystem (T cells, in particular) in Rett patients contributes, at least in part, tosome aspects of disease progression. Thus, if T cell function is improved, thedisease can be attenuated and some symptoms might be ameliorated.

15

In vivo screen of drugs and drug-like compoundsAndrew Pieper, M.D., Ph.D., University of Texas SouthwesternMedical Center in Dallas

This project tests FDA approved drugs and compounds of interestin mice models of Rett to identify Hits that improve disease-relatedsigns in the animals. Compounds that alleviate the symptoms orprogression of the disease in mice will form the basis of advanceddrug discovery programs; approved drugs can be fast-tracked toclinical trials.

mGluR5 Signaling – Is it Implicated in Rett?Mark Bear, Ph.D., MIT

Dr. Bear is a pioneering researcher whose thoughtful insight has dramatically advanced the understanding ofFragile X. His seminal work was recently featured in Forbes. Like Rett Syndrome, Fragile X is a single genedisorder, but caused by mutations in a gene called Fmr1. When Fmr1 is mutated, protein synthesis fails toshut down leading to an excess. Some years ago Dr. Bear proposed that compounds which can block a cer-tain type of receptor, mGluR5 (which triggers the burst of synaptic protein synthesis) might counteract over-expression of protein and thereby cancel out the damaging effect of Fmr1 deficiency. His theory has provedcorrect and clinical trials of mGluR5 antagonists are currently ongoing at multiple pharmaceutical companies.Dr. Bear has proposed that just as Fragile X is due to over-synthesis of proteins at the synapse, Rett may bedue to under-expression of protein at the same locations. RSRT has committed funding to the Bear lab to firsttest this hypothesis and if proven correct to explore whether pharmacological manipulations of mGluR signalingwill improve any of the mutant mice Rett-like symptoms.

Creating of Mecp2/Fmr1 double mutantsAdrian Bird, Ph.D., University of Edinburgh

Fragile X Syndrome is caused by defects in activity dependent protein synthesis at the synapse. Like Rett Syn-drome, Fragile X is a monogenic disorder, but caused by mutations in the Fmr1 gene. As described above Dr.Bear has proposed that just as Fragile X is due to over-synthesis of proteins at the synapse, tuberous sclerosisand Rett may be due to under-expression of protein at the same locations. A speculative hypothesis is that amouse that is Mecp2-null and Fmr1-null would have no symptoms because the two opposite defects would canceleach other out. If the double mutant mice show a clear improvement of any kind, this would constitute evidencethat these three disorders and perhaps other ASDs have related biological origins. It would be easy to imagineways of using pharmacological agents to further test proof of concept.

In vivo evaluation of specific drugs in mouse models of MECP2 disordersHuda Zoghbi, M.D., Baylor College of Medicine

The Zoghbi lab identified MECP2 mutations as the cause of Rett Syndrome in 1999 and has been very active inthe field since. This project is a thorough evaluation of specific drugs which will be tested in the various mousemodels of MECP2 disorders: the knockout, the truncated MECP2 and the MECP2 over-expressing mouse lines.Instead of completely lacking the MECP2 gene as in the knockout mouse, the truncated MECP2 mouse expressesthe first portion of the MECP2 protein. These animals have milder deficits with a much slower disease progression,and are therefore a model of milder forms of Rett Syndrome. Interestingly, too much MECP2 also causes a severeneurological disease, called MECP2 Duplication Syndrome.

OUR PROJECTS

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OUR PROJECTS

Genes that Modify MECP2 Mutations

Vitamin D therapy for MeCP2 target Irak1/NF-kB dysregulationJeffrey Macklis, Harvard University

In our previous studies, we identified a number of potential “target”genes of MeCP2 in these important cortical neurons. One of the over-expressed genes is Irak1, a component of the NFkB signaling path-way. We propose to investigate the therapeutic potential of one knowninhibitor of NFkB signaling, Vitamin D, in Mecp2 mutant mice. Our pro-posed experiments will not only add to our understanding of molecularand pathological mechanisms of Rett Syndrome, but will also poten-tially contribute to future therapeutic strategies via Vitamin D or alter-native NFkB pathway drugs.

Effect of the serotonin 1a agonist F15599 on respiration and locomotion in a mouse model of Rett SyndromeJohn M Bissonnette, M.D., Oregon Health and Science University

In ongoing experiments we find that the serotonin 1a agonist sarizotan effectively reduces apnea and correctsirregularity in Mecp2 deficient female mice. Sarizotan is a phase II drug that has been evaluated in clinicaltrials to treat L-dopa induced dyskinesia in Parkinson’s disease. F15599 is a serotonin 1a agonist shown to beeffective in rodent models of depression and cognition. It is an attractive candidate that may correct respiratorydisorders without affecting locomotion in Rett mice.

Novel insights in MeCP2 function suggests new therapeutic strategiesStavros Lomvardas, Ph.D., University of California San Francisco

This experiment leverages the discovery that MeCP2 deficient olfactory receptor neurons (ORN) have a very ro-bust readout; they co-express molecules that are never expressed in the same neuron in wild type mice. Dr. Lom-vardas will capitalize on this finding to screen for drugs that can reverse the deficit – in other words find drugs,using high throughput screens (HTS) that can turn off one of ectopically expressed molecular markers.

Identification of gene modifiers that ameliorate Rett symptomsMonica Justice, Ph.D., Baylor College of MedicineAn emerging field of interest is that of genetic modifiers that im-pact the severity of disease. Rett Syndrome is ideal for modifierscreening for two reasons: a) it has been shown to be reversiblein mice and b) some girls do not have Rett symptoms despitehaving common mutations in MECP2. This project aims to iden-tify these modifiers using a forward genetic screen in mice. In apreliminary screen, five lines that carry inherited suppressors,which increase lifespan and decrease other RTT-related symp-toms in mice, have been identified. As expected, most of the sup-pressors act at the level of chromatin remodeling, and may bedifficult to target therapeutically. However, one reveals a “sys-tems” component to disease pathology, and may provide a newtarget for therapeutics.

17

FINANCIALS

Rett Syndrome Research Trust, Inc.Statements of Financial Position

December 31, 2011 and 2010

Current assetsCash and cash equivalentsPromises to give

Total current assets

Other AssetsWebsite, net of accumulated amortization of $734Total other assets

Total assets

Curent liabilitiesAccounts payable Grants payable Accrued expenses

Total current liabilities

Other liabilitiesGrants payable

Total liabilities

Net assetsUnrestrictedTemporaily restricted

Total net assets

Total liabilities and net assets

2011 2010

ASSETS

LIABILITIES AND NET ASSETS

$3,588,070261,220

3,849,290

8,072

8,072

$3,857,362

$4,524 1,923,909

5,012

1,933,445

1,544,328

3,477,773

373,743 5,846

379,589

$3,857,362

$1,982,17684,179

2,066,355

-

-

$2,066,355

$4,432836,420

5,000

845,852

1,020,287

1,866,139

200,216-

200,216

$2,066,355

18

FINANCIALS

Rett Syndrome Research Trust, Inc.Statements of Activities

For the Years Ended December 31, 2011 and 2010

Public support and revenuesContributionsThe Eva Fini FundDonated services and rentInterest income Net assets released from restriction

Total support and revenue

ExpensesProgram Services

Supporting Services:Management and general Fundraising

Total Expenses

Increase in net assets from operations

Net assets (deficit)Begining of year

Net assetsEnd of year

UnrestrictedTemporarilyRestricted Total Unrestricted

TemporarilyRestricted Total

December 31, 2011 December 31, 2010

$3,527,380146,000

8,00013,082

334,536

4,028,998

3,711,210

16,748127,513

3,855,471

173,527

200,216

$373,743

$340,382---

(334,536)

5,846

-

--

-

5,846

-

$5,846

$3,867,762146,000

8,000 13,082

-

4,034,844

3,711,210

16,748 127,513

3,855,471

179,373

200,216

$379,589

$2,008,243151,808

8,000 9,145

-

2,177,196

1,534,415

15,554 54,601

1,604,570

572,626

(372,410)

$200,216

$2,008,243151,808

8,000 9,145

-

2,177,196

1,534,415

15,554 54,601

1,604,570

572,626

(372,410)

$200,216

$-----

-

-

--

-

-

-

$-

19

FINANCIALS

Rett Syndrome Research Trust, Inc.Supplemental Statement - Functional Expense Allocation and

Research Funded Expense GraphsFor the Year Ended December 31, 2011

Research Funded Expenses

Functional Expense Allocation

20

FINANCIALS

Rett Syndrome Research Trust, Inc.Supplemental Statement - Research Awards

and Grant Commitments and Payments ScheduleFor the Year Ended December 31, 2011

Baylor College of MedicineMonica Justice

Baylor College of MedicineHuda Zoghbi

Fred Hutchinson Cancer ResearchAntonio Bedalov

University of TexasSouthwest Medical CenterAndrew Pieper

University of EdinburghAdrian Bird

University of PennsylvaniaMarisa Bartolomei

University of California at San FranciscoStavros Lomvardas

Ohio State UniversityBrain Kaspar/Gail Mandel

University of VirginiaJonathan Kipnis

Weill Cornell Medical CenterRonald Crystal

OHSUJohn Bissonnette

MITMark Bear

University of North CarolinaBenjamin Philpot

HarvardJeffrey Macklis

HarvardJeannie Lee

MECP2 Consortium

Commitment at Dec 31, 2010

Additional Commitments

Payments Against Commitments

Commitment at Dec. 21, 2011

$-

25,000

187,500

166,400

908,088

10,315

17,500

13,750

46,750

504,267

-

-

-

-

-

-

$1,879,570

$298,879

517,054

-

-

-

-

-

-

440,000

-

15,147

85,896

10,000

35,352

300,000

1,840,441

$3,542,769

$(224,160)

(76,691)

(125,000)

(166,400)

(230,000)

(10,315)

(17,500)

(13,750)

(211,750)

(201,705)

(15,147)

(31,455)

(10,000)

(26,514)

(25,000)

(534,145)

(1,919,532)

$74,719

465,363

62,500

-

678,088

-

-

-

275,000

302,562

-

54,441

-

8,838

275,000

1,306,296

$3,502,807

RETT SYNDROME RESEARCH TRUST

Trustees

Adrian P. Bird, Ph.D.Professor of Genetics, University of Edinburgh

Monica CoenraadsCo-Founder, Executive Director

Heidi EpsteinFounder, Hope for Hannah

Ingrid Love HardingCo-FounderFounder and President, Girl Power 2 Cure, Inc.

Lawrence MattisFounder, Circle of Confusion

Anthony P. SchoenerVP of Engineering, Cisco Systems

Scientific Advisory Board

Adrian P. Bird, Ph.D.Professor of Genetics, University of Edinburgh

J. Michael Bishop, Ph.D.Arthur and Toni Rembe Rock Distinguished Professor, UCSFNobel Laureate

Geoff Duyk, M.D., Ph.D.Managing Director, TPG Growth

Fred H. Gage, Ph.D.Laboratory of GeneticsSalk Institute of Biological Studies

Michael E. Greenberg, Ph.D.Chair, Department of Neurobiology Harvard Medical School

Franz F. Hefti, Ph.D.VP and Chief Development OfficerChlorion Pharma

Nathaniel Heintz, Ph.D.Professor; Laboratory of Molecular BiologyRockefeller UniversityInvestigator, Howard Hughes Medical Institute

David M. Katz, Ph.D.Professor of NeurosciencesCase Western Reserve University

Christopher Lipinski, Ph.D.Melior Discovery, Inc.

Gail Mandel, Ph.D.Senior Scientist, Vollum InstituteInvestigator, Howard Hughes Medical Institute

Steven L. McKnight, Ph.D.Professor and Chairman, Department of BiochemistryUniversity of Texas Southwestern Medical Center at Dallas

Luis F. Parada, Ph.D.Professor and Chairman, Department of Developmental BiologyUniversity of Texas Southwestern Medical Center at Dallas

Huda Y. Zoghbi, M.D.Professor, Departments of Molecular and Human GeneticsPediatrics, Neurology, & Neuroscience at Baylor College of MedicineDirector, Jan & Dan Duncan Neurological Research InstituteInvestigator, Howard Hughes Medical Institute

Professional Advisory Council

Donna M. Bowers, PT, MPH, PCSSacred Heart University

James N. GianopulosChairman and CEO, Fox Filmed Entertainment

Ann GianopulosMarketing Consultant, Amplitude Consulting

Jonathan EpsteinGreenOak Real Estate Advisors LP

Stephen LevitExecutive Vice President, Chief Creative Officer, McCann

Jason M. RothschildCounsel, White & Case, LLC

Linda TaylorModel, Activist, Humanitarian and Environmentalist

Doris TulcinFounder, Cystic Fibrosis Foundation

Christopher Tuzzo

Lord Christopher WellesleyMacquarie Tristone

67 Under Cliff Road, Trumbull, CT 06611 203.445.0041

www.reverserett.org