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Over 370 registrants from 30 countries attended our 1st ever web-based Scientific Meeting!

We hope you enjoy this clip from our 2020 International Workshop,
“Researching Possibilities, ExTENding Lives” webinar

 All rights reserved. Please do not download, copy, distribute, or modify this presentation in any way.

Unanswered Chat Questions

To Dr. Francis Collins: Question: From Mansoor Amiji: Dr. Collins, have you looked at the biodistribution of the PPPMO upon systemic


Answer:
PK/PD studies indicated 100% bioavailability in heart, aorta and kidney. Kidney was the only tissue where there was a suggestion of accumulation, based on histologic examination and PK/PD data. Single dose administration of SRP-2001 demonstrated that PPMO was rapidly cleared from heart (within 2 hours), cleared from aorta within 4 hours, but sustained in kidney to the 48hr timepoint. Quantitative ddPCR demonstrated G608G cryptic splice inhibition activity in all tissues except skin tested thus far (aorta, heart, kidney, liver, quadriceps, bone), although activity varied depending on the tissue.

Francis, Mike, and Wayne

To Dr. Pinak Shah and Dr. Francesco Musumeci: Question: From RVB: Can magnesium/calcium intake determine the degree of calcification in children with HGPS?

Answer:Regarding the question, to be honest, I don’t know the answer to this question.  In a typical adult, however, we do not correlate degree of valvular calcification with Mg/Ca intake, the heavier calcification is likely due to other factors.

Dr. Pinak Shah

 

 

Answer: I agree with Dr. Shah opinion. Probably causes of valve calcification in HGPS are different from the one we see in elderly patients. I also have no knowledge on Ca and Mg metabolism.

Dr. Francesco Musumeci

 

To Dr. Vicente Andres: Question: From Andre Monteiro Da Rocha - University of Michigan: Do the mice lacking Lamin A develop DCM?

Answer: The lamin A/C null (Lmna-/-) mouse model develops DCM accompanied with loss of cardiac function. Moreover, these mice exhibit defects in cardiac conduction and extensive cardiac fibrosis, and premature death at 5-8 weeks of age (Auguste et al., 2018; Frock et al., 2012; Sullivan, 1999). However, mouse models lacking only Lamin A (Fong et al., 2006) or lamin C (Coffinier et al., 2010) do not show cardiac defects and have a normal lifespan.

References:
Auguste, G., Gurha, P., Lombardi, R., Coarfa, C., Willerson, J. T., & Marian, A. J. (2018). Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. https://doi.org/10.1161/CIRCRESAHA.117.312052

Coffinier, C., Jung, H. J., Li, Z., Nobumori, C., Yun, U. J., Farber, E. A., Davies, B. S., Weinstein, M. M., Yang, S. H., Lammerding, J., Farahani, J. N., Bentolila, L. A., Fong, L. G., & Young, S. G. (2010). Direct synthesis of lamin A, bypassing prelamin a processing, causes misshapen nuclei in fibroblasts but no detectable pathology in mice. Journal of Biological Chemistry, 285(27), 20818–20826. https://doi.org/10.1074/jbc.M110.128835

Fong, L. G., Bergo, M. O., Young, S. G., Fong, L. G., Ng, J. K., Lammerding, J., Vickers, T. A., Meta, M., Coté, N., Gavino, B., Qiao, X., Chang, S. Y., Young, S. R., Yang, S. H., Stewart, C. L., Lee, R. T., Bennett, C. F., Bergo, M. O., & Young, S. G. (2006). Prelamin A and lamin A appear to be dispensable in the nuclear lamina. The Journal of Clinical Investigation, 116(3), 743–752. https://doi.org/10.1172/JCI27125.with

Frock, R. L., Chen, S. C., Da, D., Frett, E., Lau, C., Brown, C., Pak, D. N., Wang, Y., Muchir, A., Worman, H. J., Santana, L. F., Ladiges, W. C., Rabinovitch, P. S., & Kennedy, B. K. (2012). Cardiomyocyte-specific expression of lamin A improves cardiac function in Lmna-/- mice. PLoS ONE, 7(8), 1–9. https://doi.org/10.1371/journal.pone.0042918

Sullivan, T. (1999). Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. The Journal of Cell Biology, 147(5), 913–920. https://doi.org/10.1083/jcb.147.5.913

To Dr. Giovanna Lattanzi: Question: From Tom Misteli: how long was the lonafarnib + tozilizumab treatment in animals?

Answer: We performed a preliminary experiment in heterozygous animals starting at week 22 up to week 30. We wish to focus on this time frame to evaluate the effect on weight gain that was previously observed with tocilizumab.

To Dr. Giovanna Lattanzi: Question: From Sgonzalo: Beautiful story Giovanna and Sammy!!! Did you see any side effects of tocilizumab treatment? Or any phenotypes that were not improved in progeria mice? To Dr. Giovanna Lattanzi: Question: From tom misteli: how long was the lonafarnib + tozilizumab treatment in animals?

Answer: Thank you Susana. No, we did not see any side effect of tocilizumab.  Among the examined phenotypes (kyphosis, adipose tissue dystrophy, hair and skin defects, locomotor activity, aorta lesions and myocardium hyperthrophy) were delayed/improved.

Comment: From  MARIE GERHARD-HERMAN : Also used in US for rheumatologist disease and vasculitis

Reply: Thank you Marie for this interesting info on the use for vasculitis.

Comment: From pc stefano: Tocilizumab is also approved in Japan for treating Castleman disease with no immunosoppressive effects

Reply: Thank you Stefano for these infos.

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From Delphine Larrieu: do you see any DNA damage decrease upon progerinin treatment in HGPS cells/HGPS mouse models?

Answer: We observed that DNA repair related genes(BRCA1, Rad51, etc) were altered after treatment with progerinin

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From Delphine Larrieu: How does progerinin work in Werner Syndrome that - as far as I know - does not express progerin? Does the molecule has any other targets?

Answer: WS cells can also produce a small amount of progerin like as normal aged cells. We observed progerin expression in WS cells at mRNA levels.

We think that WRN protein can function to inhibit progerin. However, in the case of WS patients, since there is no WRN protein, progerin expression is thought to occur in the 20s and 30s, as much as it is seen in normally aged people.

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From Bob Bishop: Is the progerinin binding site defined biochemically or structurally? Is there a biochemical assay to find additional compounds with this mechanism?

Answer: We performed biotin-avidin bead pull-down assay and observed the specific interaction of perogerinin with progerin but not with lamin A, lamin B, p53, or emerin.

We also perfomed Elisa assay to find additional compounds which could be putative progerin/lamin A-binding inhibitors. Progerin recombinant. be putative progerin/lamin A-binding inhibitors. Progerin recombinant protein was incubated sequentially with a chemical library and lamin A. However, progerinin was the most effective chemical in the chemical library.

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From john cooke: Great progress Dr. Kim. Does Progerinin reduce the secretion of SASP cytokines?

Answer:  We observed that progerinin could reduce the expression of IL6 and IL8 in HGPS cells.

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From Susan Michaelis: is progerinin available to researchers?

Answer: Of course, it is available if you request.

To Dr. Minju Kim and Somi Kang who presented on behalf of Dr. Bum-Joon Park Question: From Thomas W Glover: I may have missed it but what do you think is the mechanism responsible for the beneficial effects in Werner syndrome?

Answer: WS patients-derived cells also produce a small amount of progerin, as much as normal cells derived from aged people. Progerinin can be also effective in WS cells by reducing progerin expression.

A Sampling from the Chat Comments!

An honor to meet the Basso and Peraut family.  Thank you for sharing your journey.  You are truly and inspiration!

Thank you Sami and Alexandra’s family for being part of the workshop and sharing your inspirational journey with progeria!

Fantastic progress Eiger with approval on the horizon.

Can we extend this session to the end of the week and keep the discussion going?  (THANK YOU, one and all!) 

This workshop was incredible.  I congratulate the PRF for having the commitment to do this great activity.  Without a doubt, this workshop filled me with a lot of knowledge for my future.  It was amazing. Together we will find the cure!

Always impressed by the exciting science at the PRF meetings. Many kudos to the organizers for preserving the community workshop experience even in this virtual format!

You all ROCK!!! Thanks for this great opportunity, thinking about many years ago, now it is like to live in the future! Happy to be part of it

I miss Dr. Collin’s guitar. Great job!

Thank you so much for organizing this, truly the highlight of my week!

Thanks to everyone and see you in person next year in Cambridge!!

 Thank you all for joining us!