SINCE 2010 MDS FAMILIES AND THEIR NETWORKS HAVE RAISED over 5 MILLION Dollars, 100% OF WHICH SUPPORTS ONGOING RESEARCH.

CURE MDS (FORMALLY “THE 401 PROJECT”) FUNDED THE CRUCIAL EXPERIMENT IN THE LAB OF HUDA ZOGHBI THAT DETERMINED THAT MDS IS REVERSIBLE

We will not rest until we have a cure.

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Imagine.

Imagine being in a body that doesn't align with your mind. Imagine wanting to do things others do mindlessly, like walk, talk, use the bathroom, and feed yourself. But you have to work 10x harder to do them, if you ever even can. But you want to. And you try. You try so so hard. Now imagine the progress you worked so hard to accomplish, being ripped away from you eventually. Usually not all at once, but bit by bit.

Unfortunately, that is the reality majority of children diagnosed with MECP2 Duplication Syndrome face.

Now imagine being a parent of one of these children. But imagine. Imagine hearing there is hope, a potential treatment (or two or even three!) on the horizon - they just need funding. Wouldn't you do everything you could to try raise awareness and raise money to get this treatment to your child?

I have been thinking about this for awhile and it makes me unbearably emotional. A lot of us hear, "you have to live in the moment". And we do our absolute best, believe me.

But most of us know, without this treatment, we are just waiting for "the other shoe to drop".

But I often imagine what it would be like after the treatment. I imagine having a conversation with my son. I imagine him saying, "I love you." I imagine him running in the backyard playing with the dogs or hitting a tee-ball. I imagine us walking through Target and him telling me what toy he wants.

I imagine him living a life free of suffering. I imagine him getting the opportunity to live a full and happy life.

...just imagine.

MECP2 Duplication Syndrome is reversible

The symptoms that arise from the MECP2 Duplication Syndrome (MDS) are caused, as the name suggests, by having a section of the X chromosome (Xq28) erroneously duplicated. The duplicated section, which always includes the MECP2 and IRAK1 genes, varies from individual to individual and may contribute to the severity of the disease. The duplication leads to excessive levels of the MeCP2 protein as well as too much IRAK1 and potentially other proteins that are involved in the duplicated section.

Efforts aimed at addressing the root cause of MDS, too much MeCP2 protein, offer the best chances of dramatically improving symptoms of the disorder. Whether a full cure can be developed, and if so for what ages, remains to be seen. Our goal however is a cure.

There are a number of potential therapeutic strategies to lower levels of MeCP2. Since it is impossible a priori to know which strategy will ultimately be the one that works the best, it is in the interest of patients and their families that all strategies be implemented in parallel. This will lead to a diversified portfolio of potential therapeutics and increase the chances of success.

Ronald Cohn, MD | The Hospital for Sick Children

$570,000 AWARDED

UPDATED 2023.04.16

MECP2 duplication syndrome (MDS) is a brain development disorder caused by having an extra copy of the MECP2 gene. There is also always an extra copy of a nearby gene called IRAK1. However, current animal and cell models for this condition only study the effects of extra MECP2 without considering IRAK1. To better understand the role of IRAK1 in MDS, our lab has created a special mouse model with extra copies of both MECP2 and IRAK1 genes. This allows us to better study the disease and test potential treatments.

We found that our special mice with extra MECP2 and IRAK1 genes showed disease signs that got worse as they aged. At 10 weeks old, these mice had larger brains compared to their body size, and were more active and less anxious than normal mice. As they got older, the differences became more pronounced. They had lower body weight and poorer balance at 52 weeks old. These mice also lived shorter lives, similar to what is seen in human MDS patients.

Because MDS affects brain development, we tested the learning abilities of our mouse model. When we put the mice through a fear-learning test, they showed abnormal learning behavior, reacting more strongly to cues that reminded them of an unpleasant experience. We also found that their brain cells had increased signaling between them, which could be the reason for the abnormal learning behavior.

We also tested how these mice responded to the flu virus, since the IRAK1 gene is involved in controlling inflammation. The mice with extra MECP2 and IRAK1 genes had a stronger immune response to the virus. This has not been seen in other mouse models with only extra MECP2, so it could be because of the extra IRAK1 gene in our model.

To better understand the roles of MECP2 and IRAK1 in MDS, we would like to create new mouse models with extra copies of only MECP2 or only IRAK1. By comparing the behaviors, brain function, and immune responses of these new mice to our original mouse model, we can figure out how much each gene contributes to the disease.

Now that we have a mouse model that represents the human MDS condition better, we can use it to test a new treatment based on the CRISPR gene-editing technology. This treatment aims to remove the extra MECP2 and IRAK1 genes. We have found a way to do this in cells in the lab, and our next step is to try it in the mice. We will then see if this treatment can reverse the disease signs in the mice

Huda Zoghbi, MD | Baylor College of Medicine

$1,485,949 AWARDED

MECP2-duplication syndrome (MDS) occurs when there are one or more extra copies of the MECP2 gene. The excessive MeCP2 protein made by the extra copy of the gene severely affects brain function. During the previous RSRT-funded project, the Zoghbi lab discovered that MDS symptoms can be eliminated in mice if MeCP2 levels are corrected. A drug to lower MeCP2 would be the simplest way to do this for patients, so for this project the goal is to find drugs that can reduce MeCP2 protein levels or identify good drug targets that can be used to design drugs to treat MDS.

Two major approaches to find drugs that lower MeCP2 are being pursued.

1. Testing almost all of the current FDA-approved drugs to see if any of them can affect MeCP2 levels. Such strategies have worked to find treatments for other diseases, and if one is found, the path to clinical use will be dramatically accelerated since the drug will already be available and its safety profile will be known.

2. Testing every gene in the genome to identify those that regulate MeCP2 levels. Once MeCP2 regulators are identified efforts to find drugs that might inhibit them can then be sought. This approach was pilot tested and indeed several MeCP2 regulators were found. A drug to inhibit one of regulators was then tested in MDS mice and some of the mice’s symptoms were improved. For this project, all the regulators will be followed up as well as any new ones discovered, with additional mouse studies to determine which are the best drug targets and if they can work even better when used in combination.

The Zoghbi lab is trying to find as many drug targets and drugs as possible to maximize chances of finding those that are most effective and safe, and can be brought to the clinic to treat ­MECP2-duplication syndrome.

ANASTASIA KHVOROVA, PHD | UMASS MEDICAL CENTER

$799,445 AWARDED

MECP2 Duplication Syndrome (MDS) is caused by a genetic error resulting in a duplicated section of the X chromosome that includes the MECP2 gene. A promising approach to treating MDS is to reduce levels of the MECP2 protein by silencing gene expression. Gene silencing can be compared to turning down the volume on your phone, radio, or TV. Some silencers are weak and reduce gene expression only a small degree, like turning the volume down a little, while others are quite potent and result in no detectable gene expression like turning the volume all the way down.

One way to silence genes is through small interfering RNA oligonucleotides (siRNAs). siRNA interferes with the translation of targeted proteins by binding to and promoting the degradation of their RNA. In Dr. Khvorova’s project an MECP2 siRNA will guide molecular scissors to the MECP2 RNA for destruction, thereby reducing the level of MECP2 RNA in the cell.

Dr. Khvorova has developed a new RNA interference scaffold that in animal models shows robust siRNA distribution throughout the brain and spinal cord. Her approach suggests that the siRNA treatment would need to be dosed every 9 to 12 months in humans and may have a better safety profile than other forms of gene silencing.

Dr. Khvorova is a pioneer in the field of oligonucleotides and is part of the RNA Therapeutics Institute at UMASS that brings together a critical mass of scientists with RNA expertise, including Nobel laureate Craig Mello. The Institute has a strong emphasis on developing therapeutics for neurological disease.

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