A New Treatment for Sickle Cell Disease

and β-Thalassemia

2023/11/13, Zi-Hong Xiao

Sickle Cell Disease (SCD)

https://www.frontiersin.org/articles/10.3389/fmed.2023.1141020/full

 β-Thalassemia(TDT)

https://www.challengetdt.com/genetics-and-pathophysiology

Treatments for SCD/TDT

Question

The symptoms of both sickle cell disease and β-Thalassemia begin to occur six months after the child is born, why?

Hemoglobin Switch

https://www.facebook.com/StudentMidwifeStudygram/photos/a.215950679010676/720057035266702/?type=3

Hemoglobin Switch

https://uoftmedicalgenomics.home.blog/2022/05/24/competitive-transcription-factor-binding-regulates-hemoglobin-switching/

CTX001 (exa-cel)

H. Frangoul, D. Altshuler, M.D. Cappellini, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia

N Engl J Med, 384 (3) (2021), pp. 252-260

CTX001 (exa-cel)

H. Frangoul, D. Altshuler, M.D. Cappellini, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia

N Engl J Med, 384 (3) (2021), pp. 252-260

Results-TDT

Results-SCD

Newer Results

• CLIMB-111(TDT)
  • 27 patients
  • mean transfusion independent duration after infusion: 20.5 months(max. 40.7 months)

• CLIMB-121(SCD)
  • 17 patients
  • mean VOC-free duration after infusion: 18.7 months (max. 36.5 months)

Recent Progress

• FDA will decide the approval of exa-cel for SCD before 2023/12/8 and the approval of exa-cel for TDT before 2024/3/20.

• Another possible gene therapy for SCD and by inducing fetal hemoglobin.
  • CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease (2023/8/31,NEJM)

References

• H. Frangoul, D. Altshuler, M.D. Cappellini, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med, 384 (3) (2021), pp. 252-260

• A. Sharma, J. Boelens, M. Cancio et al. CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. N Engl J Med 2023; 389:820-832 DOI: 10.1056/NEJMoa2215643

• wikipedia: https://en.wikipedia.org/wiki

Brains in Sync

2024/4/29, Zi-Hong Xiao

同步(n.)

Outline

• Behavioral Synchrony
   
• Inter-Brain Synchrony
   
• When would brains get in sync?
   
• Why would brains get in sync?

behavioral synchrony

https://www.keenfootwear.com/blogs/keen-blog/got-12-minutes-get-walking

behavioral synchrony

walking in steps

walking naturally

avg. num. chosen: 3.6

avg. num. chosen: 5.4

Wiltermuth, S. S., & Heath, C. (2009). Synchrony and Cooperation. Psychological Science, 20(1), 1-5. https://doi.org/10.1111/j.1467-9280.2008.02253.x

Heart rates also get in sync!

Helm, J. L., Sbarra, D., & Ferrer, E. (2012). Assessing cross-partner associations in physiological responses via coupled oscillator models. Emotion, 12(4), 748–762. https://doi.org/10.1037/a0025036

Do brains get in sync?

A research published on Science(1965)

T. D. Duane, Thomas Behrendt
Science, New Series, Vol. 150, No. 3694 (Oct. 15, 1965), p. 367 (1 page)

New Hyperscanning Methods

fMRI

https://nirx.net
https://www.ndcn.ox.ac.uk/divisions/fmrib/what-is-fmri/introduction-to-fmri

fNIRS

Brains do get in sync!

Artur Czeszumski, Sophie Hsin-Yi Liang, Suzanne Dikker, Peter König, Chin-Pang Lee, Sander L. Koole, Brent Kelsen

Cooperative Behavior Evokes Interbrain Synchrony in the Prefrontal and Temporoparietal Cortex: A Systematic Review and Meta-Analysis of fNIRS Hyperscanning Studies
eNeuro 1 April 2022, 9 (2) ENEURO.0268-21.2022

What causes the brain to sync?

Studies show that eye contact, synchronized movements, and sharing goals are important for interbrain synchrony.

Kelong Lu, Ning Hao, When do we fall in neural synchrony with others?, Social Cognitive and Affective Neuroscience, Volume 14, Issue 3, March 2019, Pages 253–261, https://doi.org/10.1093/scan/nsz012

Perhaps brains get in sync just because people are responding to a shared environment?

Mutual Brain Machine

https://www.suzannedikker.net/mutualwavemachine

Solve puzzle together v.s. apart

Frank A Fishburn, Vishnu P Murty, Christina O Hlutkowsky, Caroline E MacGillivray, Lisa M Bemis, Meghan E Murphy, Theodore J Huppert, Susan B Perlman, Putting our heads together: interpersonal neural synchronization as a biological mechanism for shared intentionality, Social Cognitive and Affective Neuroscience, Volume 13, Issue 8, August 2018, Pages 841–849, https://doi.org/10.1093/scan/nsy060

Why would brains sync?

Advantages of Interbrain Synchrony

• Better learning
• Better communication
• Better cooperation

Perhaps interbrain synchrony is just a measure of engagement?

Dual Brain Stimulation

Dual brain stimulation enhances  inter-brain synchrony.

p < 0.01

Yafeng Pan, Giacomo Novembre, Bei Song, Yi Zhu, Yi Hu, Dual brain stimulation enhances interpersonal learning through spontaneous movement synchrony, Social Cognitive and Affective Neuroscience, Volume 16, Issue 1-2, January-February 2021, Pages 210–221, https://doi.org/10.1093/scan/nsaa080

Liu, J., Zhang, R., Xie, E. et al. Shared intentionality modulates interpersonal neural synchronization at the establishment of communication system. Commun Biol 6, 832 (2023). https://doi.org/10.1038/s42003-023-05197-z

Take-Home Message

• Inter-brain synchrony refers to the correlation of brain activity across two or more people.
   
• Inter-brain synchrony happens when people interact with each other, and eye contact, synchronized movements, and shared goals might be important.
   
• Inter-Brain synchrony might help people learn, communicate, and cooperate better.
   
• Disclaimer: These experimental results are pretty new, and might need to be further verified.

Other References

• Wikipedia: Neural Synchrony
• Quanta Magazine:  The Social Benefits of Getting Our Brains in Sync

Human Birth Defects

2024/5/17, 蕭梓宏

https://www.cdc.gov/ncbddd/birthdefects/facts-about-neural-tube-defects.html

Birth Defects?

• Birth defects are abnormal conditions present at birth.
• Causes of birth defects:
  • Genetic Factors
    • Chromosomal Abnormalities
    • Gene Mutations
  • Enviromental Factors
  • Multifactoral Inheritence (Genetic+Enviromental)

Chromosomal Abnormalities

• Include numeric/structural abnormalities
• Example: Cat Eye Syndrome(CES)
  • Prevelance: about 1/100,000 live births
  • Cause: a bisatellited supernumerary chromosome 22 resulting in a partial tetrasomy

 iris coloboma(cat eye)

Other Symptoms of CES

• Anal atresia (Imperforate anus)
• IUGR (In Utero Growth Retardation)
• Renal hypoplasia/aplasia
• Ear tag/Ear pit
• ...

https://www.mountsinai.org/health-library/symptoms/ear-tag

"We're all beautifully flawed." — Caitin Stickels, a model with CES

Mutant Genes

• Include substitutions/indels
• Example: Piebaldism
  • Prevelance: less than 1/20,000 live births
  • An autosomal dominant disorder

https://nypost.com/2020/11/16/boy-with-rare-skin-condition-becomes-supermodel-and-it-runs-in-his-family/

Piebaldism

• Cause:
  • Mutation of the KIT gene or the SNAI2 gene
    • Might be a substitution, insertion, or deletion.
    • Both genes are important for the development of melanocytes.
• The depigmented areas of piebaldism are usually benign and stable.

Enviromental Factors

• Teratogens include alocohol, drugs, infections, ...
• Example: Fetal hydantoin syndrome
  • Caused by exposure to phenytoin

Phenytoin, an anti-seizure drug

Symptoms of Fetal Hydantoin Syndrome

• IUGR
• microcephaly
• cognitive deficiency
• abnormal hearing
• eyelid ptosis
• broad nasal bridge
• ...

https://obgynkey.com/environmental-agents/

Multifactorial Inheritance

• Genetic and enviromental factors acting together
• Example: Infantile hypertrophic pyloric stenosis (IHPS)

https://radiopaedia.org/articles/pyloric-stenosis

Infantile Hypertrophic Pyloric Stenosis

• Prevelance: about 2/1000 live births
• Cause:
  • Multiple genes are asscoiated with IHPS 
    • AOPA1, BARX1,...
  • Smoking during pregnancy increases the risk of IHPS.
• Symptoms:
  • Projectile vomiting
  • Dehydration
  • ...

https://healthjade.net/projectile-vomiting/

References

• Heather E. McDermid, Bernice E. Morrow, Genomic Disorders on 22q11, The American Journal of Human Genetics, Volume 70, Issue 5, 2002, Pages 1077-1088
• Fadista J, Skotte L, Geller F, Bybjerg-Grauholm J, Gørtz S, Romitti PA, Caggana M, Kay DM, Matsson H, Boyd HA, Hougaard DM, Nordenskjöld A, Mills JL, Melbye M, Feenstra B. Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis. Hum Mol Genet. 2019 Jan 15;28(2):332-340. doi: 10.1093/hmg/ddy347. PMID: 30281099; PMCID: PMC6322072.
• Wikipedia: https://www.wikipedia.org/
• Genetic and Rare Diseases Information Center https://rarediseases.info.nih.gov/

Thank you!