Cure AP-4

Thank you so much Patient Worthy and Jessica Lynn for sharing our story!

From SPG47 Diagnosis to Rare Disease Research - Patient Worthy Kasey discusses her daughter's hereditary spastic paraplegia SPG47 diagnosis, the development of Cure AP-4, and rare disease research.

New publication out!

So, so grateful to Dr. Ebrahimi, Fakhari, and the Cure AP -4 team for all of their hard work and dedication!

Using ChatGPT, I asked it to turn the abstract paragraph into understandable terms for non-medical professionals.

Here it is:

In our study, we did a big experiment to find treatments for rare diseases. We focused on a rare childhood disease called AP-4 deficiency, which affects the movement of a special protein in the body. We tested over 28,000 different tiny molecules to see if any could fix this problem. We found one, named B*H-HSP-C01, that worked really well. It helped fix the protein issue in cells taken from patients and in special lab-made nerve cells. We also did more tests to understand how B*H-HSP-C01 works. Our findings are a big step in finding a treatment for AP-4 deficiency and show how this method can help with other rare diseases too

High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking ...

So excited about this partnership!!!!!

CURE AP-4 ENGAGES UNRAVEL BIOSCIENCE IN PIONEERING AI-DRIVEN DRUG DISCOVERY FOR ULTRA-RARE CNS DISEASE Partnership will generate clinical data from patients globally to accelerate identifying and developing therapeutics for AP-4 hereditary spastic paraplegias.

There’s still time to order! Our Kendra Scott fundraiser ends on Friday, 9/8! Thank you so much to everyone who ordered already! Calls will be made on 9/11 to everyone who has placed an order for payment.

To place your order: click👇🏻

https://forms.office.com/r/RYXmC1m055

Thank you, as always, for your support in our mission to Cure SPG47! 💙💚+💛

Please join us in supporting our mission to cure SPG47!

Our annual Kendra Scott fundraiser is live and Molly once again picked some great pieces!

Scan the QR code in the picture or click the link below to order! Orders will be taken through 9/8 & you will be called during the week of 9/10 for payment. 20% of all sales will be donated to our nonprofit, Cure SPG47!

https://forms.office.com/r/RYXmC1m055

*If you would like to purchase any additional jewelry from their site, you can call the Ardmore location (610-726-1838) to place your order and it will be included in the donation.

Updated video with even more special moms!

Special moms video

EXCITING grant funding announcement (over $1,000,000!) for our Cure AP-4 Team across the pond in England, through LifeArc’s Philanthropy Fund!

I haven’t meant to ignore these incredibly important people in our Village. I’ve been waiting for the go-ahead to share, and what better timing with Rare Disease day on Tuesday!

This heroic team is led by Principal Investigator Dr. Mimoun Azzouz, and includes his brilliant researchers out of the Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield.

Dr. Azzouz is pioneering innovate gene therapy research for a range of genetic neurological conditions. Current funding from LifeArc’s Philanthropic Fund (£470,066 -just over $600,000 USD- allocated in 2020) has allowed Dr. Azzouz to provide proof-of-concept evidence about the potential to restore the AP4B1 gene through gene therapy. Based on the results, further funding of £881,178 (about $1,058,572 USD) from the Philanthropic Fund has been awarded to Dr. Azzouz in order to produce the gene therapy batches under clinical grade manufacturing required to move on to clinical trials in the near future.

LifeArc is an independent medical research charity helping turn promising science into benefits for patients. The LifeArc Philanthropic Fund supports, through grants, translational rare disease research projects focused on developing an intervention (therapeutic, device or diagnostic) that will address a significant, unaddressed need for rare disease patients and on research which has a credible translational and development path to reaching those patients. https://www.lifearc.org

The University of Sheffield has won awards recognizing it as a centre for excellence in neuroscience research and teaching, where their researchers are making life-changing discoveries and progress in treating some of the most devastating neurological diseases, and making a real difference to patients’ lives. https://lnkd.in/edWbk2mW

We are simply overjoyed with gratitude and appreciation to both Dr. Azzouz, for the required (and tedious) time and effort he put in to achieve this funding, and to LifeArc, for not just recognizing this great need in the rare disease community, but for choosing Dr. Azzouz’s research, our children’s research, as one of so many worth putting funding towards. Our optimism is once again bolstered by the INCREDIBLE support and work our research teams have shown time and time again.

I've been taking a walk down memory lane recently. Can you believe this is how it all started?

Exciting new publication from our AP4B1 gene therapy Principal Investigator, Dr. Mimoun Azzouz, out of Sheffield Institute for Translational Neuroscience (SITraN) on the AP4B1 knock-out mouse model.

"this study provides strong evidence for the use of this model for further research into the aetiology of adaptor protein Complex 4 deficiency in humans, as well as its use for the development and testing of new therapeutic modalities."

Ap4b1-knockout mouse model of hereditary spastic paraplegia type 47 displays motor dysfunction, aberrant brain morphology and ATG9A mislocalization Scarrott et al. report a recently generated clustered regularly interspaced short palindromic repeat-mediated mouse model of hereditary spastic paraplegia 47 di

A huge CONGRATULATIONS to a very important, and very beloved, AP-4 researcher, Dr. Alex Davies.

In January 2017, when we had just started our research and just learned of Alex, a post of hers on Twitter softened some anxieties; "Molly & Robbie are my inspiration ❤". This was one of the first experiences of many reassuring us we are not alone in our plight.

Since then, she's made significant therapeutically relevant findings related to the molecular and cellular underpinnings of AP-4-HSP.

In February, she will be joining the University of Manchester, Division of Molecular & Cellular Function as a Lecturer and Group Leader. Her lab will work on neurological disorders caused by defects in protein trafficking, initially focusing on early-onset HSPs.

While we are always cautiously optimistic, reading this sentence in Dr. Davies's publication "AP-4-mediated axonal transport controls endocannabinoid production in neurons" was thrilling: "Together, these data suggest that 2-AG levels are limiting for neurite outgrowth in AP-4-deficient iPSC neurons and indicate that MGLL inhibition could be a therapeutic avenue for AP-4 deficiency syndrome.”

I’m not sure I have the words to adequately express my gratitude and overall feelings on our Golf for a Cure event on Tuesday. It could not have been more perfect. The generosity and kindness shown to my family leaves me in awe. Friends and family traveled from near and far to support us. It was amazing to spend the whole day with Kasey! We had the most perfect weather and even had a visit from the Philly Phanatic! It is a little early to have a final tally, but I think this may have been our biggest year yet. I am continually amazed that this event alone has raised well over $1,000,000 since we started! Huge shoutout to the members and staff from Riverton Country Club, family & friends for all of their incredible support and love! 💙💚

It’s that time of year again! Our 6th Annual Golf for a Cure event is coming up on September 20th and Molly designed some new pieces of jewelry at Kendra Scott!

In addition to the pieces Molly created, Kendra Scott will donate 20% of ANY purchase you make to Cure SPG47 either through their website (www.kendrascott.com) or over the phone (610-726-1838) using the giveback code GIVEBACK-CLYXJ now through 9/20!

***Just a quick tip: If you are purchasing Molly’s jewelry picks online, visit www.kendrascott.com, click on the menu and find “customize.”
• From there, you will be able to find the Elisa Necklace, the Logan Stud Earrings, and the Elaina Multi Strand Bracelet.
• Molly’s stone choices for all 3 styles are either Periwinkle Cats Eye or Chalcedony!

Please let me know if you have any questions at all or if you need help navigating the custom pieces on the website. Thank you as always for you continued support!

This is more than exciting- this is AMAZING!

What better time than Rare Disease Day to post this new publication suggesting a possible therapeutic avenue for our AP-4-HSP kids?

"MGLL inhibition rescues neurite growth in patient neurons"
https://www.nature.com/articles/s41467-022-28609-w

I have happy tears! Dr. Alexandra Davies has been indispensable to our Cure AP-4 community and research. Not only is she an amazingly kind and lovely individual, her brilliance speaks for itself!

Among other AP-4 discoveries, her postdoctoral work has uncovered a role for AP-4 vesicle trafficking in the spatial control of endocannabinoid signalling which, in turn, has led our researchers towards a potential therapeutic to address the neurite growth defects seen in AP-4-HSP. Absolutely INCREDIBLE!

EXCITING DEVELOPMENTS! 2021 Cure AP-4 Research Updates

Worth a full read, but here are the bullet points:

*Gene Therapy: AP4B1 protein rescue observed in multiple efficacy studies!

*Drug Screening: Compounds have been identified that are functionally restorative in vitro, including a drug already being tested for treatment of another medical issue in on-going human clinical trials that has proven safe thus far!

*International AP-4-HSP Longitudinal Natural History Study: Not a progressive demyelinating disorder! Their brains develop with less myelination than normal but they are not expected to lose myelination, thus being able to retain cognition gained despite motor skill loss!

When my husband and I, along with Kevin and Angela Duffy, founded Cure SPG47 (now Cure AP-4) in 2016, we were panic-stricken. We were afraid of the known, and the unknown, of our daughters’ ultra-rare neurodegenerative disease diagnosis. The World Wide Web’s informative contribution was dishearteningly meager. Though we felt broken, we also felt an unconditional love for our girls, from which emerged great hope, passion, and, above all, perseverance towards a shared goal: identifying therapeutic intervention to slow down or stop the predicted degeneration of this condition.

Five years later, we are buoyed by more than our hope. We are now blessed to have our “Cure AP-4 Team” of researchers whose own reservoir of grit and passion is astonishingly robust, as is their combined knowledge in understanding this disease and identifying potential therapies. The updates from this year’s Cure AP-4 research conference bolster greatly our optimism that treatment may be identified in a meaningful timeframe for our AP-4-HSP kids.

GENE THERAPY: Cure AP-4 initiated a gene therapy proof-of-concept effort under the direction of Dr. Mimoun Azzouz at the University of Sheffield, UK in 2017. The resulting therapeutic entity shows promise in multiple efficacy studies. Toxicity studies in mice and non-human primates are scheduled to begin soon, and planning for a phase 1 human clinical trial is currently underway.

DRUG SCREENING: Due to the loss-of-function of any of the AP-4 subunit genes (AP4B1, AP4E1, AP4M1, or AP4S1), a protein known as ATG9A, with an imperative role in autophagy (recycling of macromolecules so that cells stay healthy) is unable to be transported to where it needs to go in order to do its job. This dysfunction is implicated as being the leading cause of AP-4-HSP’s degenerative properties.

Dr. Ebrahimi-Fakhari and his team out of the Rosamund Stone Zander Translational Neuroscience Center at Boston Children’s Hospital have identified a set of small molecules that lead to redistribution of ATG9A in patient cells, including skin cells and cultured neurons. They are now testing these compounds in several assays to determine the mechanism of action and to optimize these compounds before moving into testing in a zebrafish model and, eventually, in mice.

Additionally, and also very exciting, Dr. Alex Davies, our molecular and cell biologist out of the Max Planck Institute for Biochemistry, has identified an important cargo of the AP-4 sub-unit that, like ATG9A, is also not being properly transported to where it needs to perform its duty. This cargo, an enzyme called DAGLB, plays a critical role in a process involved in neuronal growth and branching in early brain development. This discovery offers an entirely new target for treatments. With much serendipity, there is a drug currently involved in on-going clinical trials (for a different therapeutic target) that may compensate for this loss of DAGLB. So far, the clinical trials have raised no safety concerns. Compellingly, a validation of this drug in cultured neurons from patients has shown a positive effect on neurite outgrowth. Future studies in animal models are needed to evaluate if this target can help reverse some of the neuronal changes seen in AP-4-HSP patients.

NATURAL HISTORY STUDY: Dr. Darius Ebrahimi-Fakhari continues to monitor the effect and spectrum of this disorder and it’s progression as patients age. Globally, there are now 239 AP-4-HSP patients registered. His work is helping to inform much about this disorder, including new discoveries in a common diagnostic imaging signature in the brain, as well as what comes as a great relief to us parents: AP-4-HSP is a disorder of myelination rather than a progressive demyelinating disorder. Physically, our children may experience regression in motor skills but mentally, cognitively, they may not be as adversely impacted!

Fear, in our case, proved essential. In its absence, acceptance would have equaled complacency. The unknown of Molly and Robbie’s future would subsist in perpetuity. And that existence, to me, is terrifying.

So much gratitude,

Kasey Edwards

It’s no short of a miracle being where we are today compared to when we first met the Duffys. I can’t help but smile now whenever I watch this. I will forever treasure this meeting and its catalytic impact on our life’s trajectory: https://youtu.be/rkMdiSO7sL4

We just held our 5th Annual Golf for a Cure event at Riverton Country Club! This is one of my favorite days of the year because it reminds me of how much good there is in the world. The continued support shown to our family and those impacted by SPG47 by this small, yet amazing community is a truly humbling experience.

In 2017, our first year, we set a goal hoping to raise $50,000 and far surpassed that goal by raising an astounding $227,000! This year once again exceeded our wildest expectations by raising our highest amount yet; $255,000! In just 5 years, *really 5 days of golf,* we were fortunate to have raised $1,080,000!!!

https://youtu.be/boed-x01k50

Our family is so grateful. 💙💚

CHECK OUT THESE GRANTS AWARDED!

We all need a bit of good news lately and I am happy to oblige! We were recently informed that our team at Boston Children’s Hospital, leading investigators Drs. Darius Ebrahimi Fakhari and Mustafa Sahin, and including Dr. Ebrahimi-Fakhari’s postdoc, Dr. Afshin Saffari, and Darius’ students Martin Ziegler and Julian Alecu, have secured numerous sources of grant funding! Not only are we inordinately grateful for their hard work and research that earned them these opportunities but to the incredibly generous grantors as well!!!! This is simply astounding and so, so encouraging!

1. National Institute of Health/National Institute of Neurological Disorders and Stroke:Award
“An Unbiased Phenotypic Screen for Novel Therapeutic Targets in AP-4-associated Hereditary Spastic Paraplegia”

2. National Institute of Health/National Institute of Neurological Disorders and Stroke: Award -01
“Development of a Translational Research Platform to Understand and treat Defective Protein Trafficking in Childhood-Onset Hereditary Spastic Paraplegia

3. The Manton Center for Orphan Disease Research: “ Functional Genomic Screen in a Neuronal Model of Hereditary Spastic Paraplegia”
This project will test the hypothesis that an unbiased arrayed CRISPR-mediated loss-of-function screen can identify novel modulators of intracellular protein trafficking for the treatment of AP-4-associated hereditary spastic paraplegia, an ultrarare neurogenetic disease in children.
https://www.childrenshospital.org/research/centers-departmental-programs/manton-center-for-orphan-disease-research

4. Children’s Rare Disease Cohort Initiative: “The Early-onset Hereditary Spastic Paraplegia Sequencing Initiative”
https://www.childrenshospital.org/centers-and-services/programs/o-_-z/precision-medicine-service/rare-disease-cohorts

5. Tom Wahlig Foundation: “Characterization of ap4b1-/- zebrafish as a novel in vivo model of SPG47 and its application in small molecule screens”
This project will characterize ap4b1-/- zebrafish on a morphological biochemical and behavioral level and test novel small molecule modulators of ATG9A trafficking.
https://www.hsp-info.de/en/news/news.html?tx_news_pi1%5Bnews%5D=594&tx_news_pi1%5Bcontroller%5D=News&tx_news_pi1%5Baction%5D=detail&cHash=7ae5fa0b2cee33f2a3f64c5699f2ad15

6. German Research Foundation: Dr. Ebrahimi-Fakhari’s postdoc, Dr. Afshin Saffari, was awarded a 2-year fellowship to work on AP-4-HSP.
https://gepris.dfg.de/gepris/projekt/448402208

7. German Academic Exchange Service: Dr. Ebrahimi-Fakhari’s students Marvin Ziegler and Julian Alecu were both awarded a Biomedical Engineering Fellowship from the to work on AP-4-HSP.
https://www.daad.de/en/

Many thanks to Jessica Pizzamiglio and beautiful Martina in Italy for their efforts in both gaining attention for SPG50 and for their goal towards raising money for AP-4 research through Boston Children's Hospital!

From Jessica's post:
"I would like to share with you the interview I did with a local television where I talk about Marty and the association I created here in Italy. I am in contact with Children's Hospital so they can start making donations for a care for all our children! If you want to watch it, you can turn on the English subtitles. I hope you like it ❤️"

https://youtu.be/Xuk-atcIbKc

TeleOrzi - Una speranza per la piccola Martina Questa è la storia di Martina, una ragazzina di 13 anni residente ad Orzinuovi (Brescia), affetta da una malattia rarissima, la SPG-50, malattia degenerativa...

Cure SPG47 has once again partnered with Kendra Scott to offer a specially designed piece of jewelry that represents our non-profit! You may recall Molly designed a bracelet a few years ago that we see people wearing to this day!

With the new addition of Molly's baby brother, Owen, who also unfortunately was diagnosed with SPG47, we thought it would be the perfect time to offer new pieces of coordinating bracelets to represent Cure SPG47 and the children impacted by this disease.

If you would like more details or to purchase the bracelet(s) to support our cause, please click the link below and submit the form by August 31, 2021. Thank you for supporting Cure SPG47!

https://forms.gle/1rQ6PFTT3uFmDkuZ8

Wow! Just wow! When we started Cure AP-4 in 2016, We were anxious and intimidated but oh so hopeful. I can’t believe how far we’ve come- a very large part accredited to the hard work and passion of our Principal Investigators and research team in general. I am feeling incredibly blessed today! Happy tears!

This just in! Our Principal Investigator at Boston Children's Hospital, Dr. Darius Ebrahimi-Fakhari, has been awarded, from the NIH, $1,000,000 (ONE MILLION DOLLARS!!!!) over the next five years towards 80% of his salary, plus a bit towards some reagent funding, specifically for his work on AP-4. This is amazing in so many ways. It's a testament to how hard Darius has worked and how much progress he's made towards understanding more about AP-4 and its role in health and disease. It also may open a gateway towards more funding in the future and puts more focus on AP-4 at the NIH. We are ecstatic!

This is wonderful news for the Translational Neuroscience Center! And those are our “Cure AP4 team” researchers wearing their fleeces with the Cure AP-4 logo that says “Cure AP-4 Team” on them! ❤️ Such incredible generosity from Rosamund Stone Zander to researchers who will do amazing things for rare disease research and discovery with this funding!

Meet the researcher! From the Translational Genomics Group/Broad Institute: Samantha Baxter is a licensed genetic counselor and the Associate Director of Genetic and Genomic Data Sharing at the Broad Institute of MIT and Harvard. As part of her Cure AP-4 research, Samantha leads a team of variant curators who use various data sources and curation processes to estimate the prevalence of rare disease in the global population. She also has a personal interest in helping patient- and family-led organizations harness the power of genomic data to help advance their mission.

Meet this researcher! From the Translational Genomics Group/Broad Institute: Moriel Singer-Berk is a clinical genomic variant curator at the Broad Institute of MIT and Harvard. As part of her Cure AP-4 research, she utilized ACMG criteria in the curation of known variation in AP4 genes, as well as performing an in depth curation for loss-of-function variants that are seen in the gnomAD database. These curation efforts were critical in estimating the prevalence of AP4 related disease in the global population. She was thrilled to be a small part of the team moving AP4 research forward.

Meet the Researcher- Paolo Marchi! My name is Paolo and I am a 3rd year PhD student in Neuroscience in the lab of Prof. Azzouz.

My current scientific research focuses on the C9orf72 mutation, which is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. I am also actively supporting our team's effort in the work on the AP-4 complex, by performing immunoblotting and immunohistochemistry analyses on AP-4 mouse model samples.

Meet the researchers! These specialists are so important in our plight for our children and so it important for me to introduce you to these brilliant minds! I would love to introduce you to Lara Mallone:

"My name is Lara and for several years, I have been interested in dissecting the molecular mechanisms of neurodegeneration to identify potential treatments. My current research focuses on SPG15 and the AP-5 protein complex, but I am actively supporting our team’s work on the closely related AP-4 complex. Since both AP-4 and AP-5 are involved in vesicle trafficking and cause spastic paraplegia when lost, I believe that lessons learnt from one complex may be relevant for the other and help elucidate shared pathways underlying disease."

This is a huge step! The AP-4-HSP Natural History Study and Registry is listed on clinicaltrials.gov. This is a milestone!

https://clinicaltrials.gov/ct2/show/NCT04712812...

Registry and Natural History Study for AP-4 Associated Hereditary Spastic Paraplegia (AP-4-HSP) - Full Text View - ClinicalTrials.gov Registry and Natural History Study for AP-4 Associated Hereditary Spastic Paraplegia (AP-4-HSP) - Full Text View.

Molly had a very exciting day yesterday! She was given her very own custom-made bike. Special thanks to Preston's March For Energy and Families Behind the Badge Children's Foundation for making this happen! It has been a much anticipated wait for this day, but for Molly to now be able to have the freedom to ride a bike like everyone else is priceless! As you can see from her smile, she absolutely loves her bike!
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Check her out on 6ABC! 6abc.com/6313047/

I am excited to announce another great researcher to the Cure AP-4 team; The AP-4-HSP Natural History Study's new coordinator, Greg Geisel.

We are very excited to have Greg join our team starting July 1st. Greg has a strong background in research and comes to us highly recommended. He is a native of Clifton Park, upstate New York.He played 4 years of collegiate level baseball, graduating in 2017 from Union College with a double major in biochemistry and economics. Years of undergraduate basic science research in hormone pathways translated to a lab technician position in infectious disease for 2 years at the Institute for Clinical Pharmacodynamics. His passion for clinical work developed through volunteering weekly at a local community-run hospice care facility in upstate NY. With plans to pursue a career in medicine, Greg joined our team at B*H where he coordinated three clinical drug trials for two rare neurologic diseases, PTEN hamartoma syndrome and Tuberous Sclerosis. We are excited that he will now coordinate our AP-4-HSP studies!