Dear Champ Supporters,
It’s been a busy few months at The Champ Foundation! We have exciting updates from our June fundraising campaign, the SLSMDS Family and Scientific Research Conference, and newly funded research projects.
June Fundraising Campaign
We held annual 22 day long fundraising campaign. In collaboration with 8 families of Pearson syndrome Champs, we raised over $67,000. Thank you! Every dollar donated will go directly to researchers working to find treatment and a cure for SLSMDS like Pearson syndrome.
SLSMDS Family and Scientific Conference
The Champ Foundation hosted a SLSMDS Family and Scientific Conference in Philadelphia, PA. Over the course of two days, we had over 100 people travel to Philadelphia to focus on single large-scale mtDNA deletion disorders, like Pearson syndrome.
Some conference highlights, by the numbers:
- More than 100 conference participants at our welcome dinner at the Philadelphia Zoo and at the scientific event at Children’s Hospital of Philadelphia
- 15 families of affected children attended our conference in person. This was the largest gathering EVER of children with Pearson syndrome and KSS
- 10 countries where attendees traveled or attended from
- 10 children who participated in research. We had a phlebotomist in the back of the conference room collecting labs and a research assistant collecting survey data. We effectively doubled our Natural History Study data in ONE DAY!
- 6 presentations by Champ grantees
- 1 mission to find treatment and a cure for SLSMDS!
Here’s what some attendees told us after the conference:
Favorite part of the conference
- Honestly, just being around other families that truly “get it.” Having a child with a rare disease can be extremely isolating. We didn't get to speak to everyone but there was a connection that we felt with all the families and even doctors that was on a entirely different level.
- I enjoyed both the research progress/plan and patient stories-the latter are truly motivating
- Joining the family's together with world-class scientists
- Seeing everyone in one space and being able to really 'see' where everything the champ foundation does goes to!
- The fact that it was casual enough that kids could be coming in and out yet professional enough that the researchers shared their projects in detail.
Most interesting thing learned
- I was encouraged by the amount of research actually happening on SLSMDS. I am intrigued by the potential of the 2DG molecule as well as the mouse model and the impact that can have on future research.
- So many things! We were so impressed by the amount of Research and support that is going into finding a cure to SLSMDS. Learning about how the disease manifests at such a microscopic level. We also really enjoyed speaking to the doctors and research team at the dinner outside of the medical office. The casual environment created a more personal connection between both patient and doctor.
- That the quality of the research funded by the foundation is excellent!
- Range of exciting therapies being developed with CHAMP Foundation funding; Risk of malignancy in PS patients higher than previously recognized
What else can The Champ Foundation be doing to help finding a cure?
- We feel like the Champ Foundation is doing an incredible job. I think they need to just continue to do exactly what they are doing because it seems to be working!
- I think the CF is a remarkable organization it has a clear commitment to fund research of the highest standard and this was strikingly evident at the meeting - across the world I have seen that not all small to medium sized foundations are run to the same high standard as major funding bodies but TCF is indistinguishable from the biggest and best. I said as much to my partner the day after the meeting.
- I think The Champ Foundation’s approach is thorough and very comprehensive! I can’t think of anything additional at the moment, keep up the amazing work.
We are funding two new projects, in our largest grant cycle to date! This is possible because of donors like you, and our collaborations with the SLSMDS Family Partnership (Luca Gargiulo Pearson Foundation and Associzione Luigi Comini Onlus). We are funding a project at the University of Pittsburgh (PI Brett Kaufman, Bruce Armitage, and Vincent Rotello) and a project at University College London (PI Ian Holt and Antonella Spinazzola). Both groups presented at our conference and the research and family communies are excited about the translational potential! Details on the project are below.
A novel mechanism to target the mtDNA common deletion
- Principal investigators: Brett Kaufman (University of Pittsburgh), Bruce Armitage (Carnegie Mellon) and Dr. Vincent Rotello (UMass Amherst)
- Institution: University of Pittsburgh
- Direct cost: $100,000 over 1 year
- Date awarded: July 2022
- Lay abstract: Mitochondrial disorders can be caused by pathogenic mitochondrial DNA (mtDNA) variation (i.e., mutation), generally in a heteroplasmic state. In heteroplasmy, some mtDNA are healthy, “good,” and some are unhealthy, “bad.” A subset of sporadic mtDNA mutations lacks a substantial portion of the normal sequence, characterized as single large-scale deletions in mtDNA, which causes progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS). There are no effective therapies or cures for patients affected by a mtDNA deletion. The inability to remove disease-causing mtDNA sequences remains a blockade in treating mtDNA-borne disorders. Evidence suggests that eliminating bad mtDNA or adding good mtDNA can cause positive effects. While other experimental approaches are being developed, effective treatment will likely require multiple approaches. We seek to develop a specific strategy to remove bad mtDNA using molecules similar to DNA called peptide nucleic acids (PNA) In the past, PNAs have been utilized to attempt to remove bad mtDNA; however, this approach failed because the PNAs could not reach the mtDNA. One additional issue with that approach is that PNAs have limited ability to penetrate genomic DNA. Recently, new chemistry and concepts involving gamma-substituted PNAs (γPNAs) have greatly improved this and have enabled whole animal DNA editing and somatic cell therapies, evidence of DNA penetration, and block of DNA replication. However, the current challenge is establishing efficient two-step delivery into the cell and then the mitochondria. In this study, we will use next-generation approaches to solve the mtDNA targeting problem for a designer γPNA sequence specific to the mtDNA “common” deletion found in patients (γ-P3). Our preliminary data shows the successful adaptation of a recently described polymer strategy that yields improved delivery of γ-PNAs into the cell. Objective 1 will develop strategies to optimize polymer-mediated delivery of a fluorescent γ-P3 and establish optimal formulations for cellular delivery. Preliminary data shows no toxicity in animal models with polymer delivery. Objective 2 will synthesize and test γ-P3 with a mitochondrial import sequence on isolated mitochondria from animals and cells to establish evidence of interaction with the “bad” mtDNA. Objective 3 will determine whether the optimized delivery of γ-P3 can reduce mtDNA common deletion from a heteroplasmic cell to improve mitochondrial function. We can directly test for γ-P3 interaction with the correct template and block of replication. Successful completion of this work will enable future in vitro studies in more relevant cell types directly applicable to patient therapy but challenging to work with for rapid γ-PNA development.
Towards eradicating mitochondrial DNA deletions via small molecule therapies.
- Principal investigators: Ian Holt and Antonella Spinazzola
- Institution: University of College London
- Direct cost: $377,955.76 over 2 years
- Date awarded: August 2022
- Lay abstract: Mitochondria are the parts of the cell that produce most of the energy we generate from food, and this process depends on the many small circles of DNA they contain - mitochondrial DNAs. Alterations (mutations) of mitochondrial DNA are among the most frequent causes of genetic diseases, which can manifest at any stage of life and can affect any part of the body. One type of these mutations, the single large-scale mitochondrial DNA deletions (SLSMDs), involves the loss of a large portion of the mitochondrial DNA and they can cause Pearson’s and Kearns-Sayre syndromes. Importantly, the deleted molecules coexist with normal copies, and mitochondrial malfunction and disease manifest when the damaged DNAs reach high levels. Consequently, finding a way to decrease the number of deleted mitochondrial DNAs and increase the good copies could radically improve the length and quality of life of patients with SLSMDs. Recently, we discovered that we can cripple mitochondria that contain one type of mutant mitochondrial DNA, while permitting those with good copies of mitochondrial DNA to thrive, using compounds that change nutrient usage inside the cell. This represents an important breakthrough in mitochondrial medicine, as the compounds could benefit patients with SLSMDs. With this project we aim to i) test the small molecules against deleted mitochondrial DNAs, in cultured cells; ii) assess the effects of one of them in a mouse that shows mitochondrial dysfunction owing to a similar kind of mutant mtDNA, and iii) discover the key changes inside the cell that select the ‘good’ mitochondrial DNAs. Achieving these goals will bring us closer to the goal of finding a cure for SLSMD Syndromes. Thank you for your continued support of The Champ Foundation. We are making progress to find treatment and a cure for SLSMDS like Pearson syndrome and KSS. We are grateful to have you in our corner.
Elizabeth and Jeff Reynolds
Co-Founders, The Champ Foundation