L24 personalized treatment minden

• poll ev

  the type of neuron that is deficient in parkinsons disease is

  • dopamine neurons

  the cell type that produces myelin is

  • oligodendrocytes

  the growth of which type of cells would be most promising for the treatment of AMD ?

  • retinal pigment epithelial cells

  how is nitric oxide (NO) related to stem cells ?

  • MSCs produce NO
  • NO —> used to suppress T cell proliferation , immunosuppressant .
  • useful bc ms is autoimmune disease
• STEM CELL APPLICATION IN DISEASE TREATMENT

  • Parkinson’s
  • Alzheimer’s
  • Multiple Sclerosis (MS)
  • Amyotrophic Lateral Sclerosis (ALS)
  • Spinal cord injury
  • Burns and skin disorders
  • Diabetes
  • Cardiomyopathy
  • Liver failure
  • Regenerative medicine
  • Macular degeneration
  • Cornea disorders
  • heart disease
  • epilepsy
• stem cell treatments

  • majority of clinical trials use ADULT STEM CELLS, ESP HEMATOPOIETIC STEM CELLS
  • treatment: non blood diseases (listed above)
  • studies still in early phases … heart disease ones are more advanced and coming along
  • procedures are now sage
  • any fda approved? only with adult stem cells
• CHALLENGES, PROBLEMS

  a.Insufficient regulation

  b. Insufficient education of patients, leading to unrealistic false hope

  c. Technical challenges with using stem cells

  d. Dealing with possible rejection by the immune system
• . Insufficient regulation

  • patient cells do not = drugs !!
  • ig kind of like the umbilical cord theory where if ur parents decide to keep your umbilical cord blood for the SLIGHT CHANCE that u might need it when u grow up and need stem cells ….but if the lab/clinic holds it for it…it might be used for another patient !
  • THERES NOT ENOUGH RULES AND REGULATION
  • MORAL OF THE STORY: OFFERING UNPROVEN TREATMENTS (that prob dont even work)
  • WASNT FDA APPROVED UNTIL 2017
  • SO CLINICS were using not fda approved stem cell therapies
  • ex. ppl lost their vision bc they got stem cells injected into eyes
• b. Insufficient education of patients, leading to unrealistic false hope

  • ppl are given false hope to be treated
  • clinics promise cell treatments and have little regulation
  • they dont deliver what they claim!

  c. Technical challenges with using stem cells (minden left off here)

  • stem cell differentiation
  • ECTODERM = OK , most straightforward
  • MESODERM = still fine , heart, vascular cells
  • ENDODERM = most DIFFICULT!! lung, pancreas
  • implantation

  d. Dealing with possible rejection by the immune system

  • n/a
• The road to the clinic

  1. basic research - study cells in lab
  2. preclinical research - test safety, efficiency
  3. clinical trials
  4. phase 1 - test therapy on small group of people
  5. phase 2 - therapy to larger group of patients to test efficacy and to test safety in more depth
  6. phase 3 - treatment given to larger group of individuals to test its efficacy. results are compared with other treatments and other trials . only of this stage is successful, will the drug or treatment go to market
  7. phase 4 - after drug is on market, assess risks and best ways to use the treatment
• stem cell therapy - treating patient with new stem cells
• stem cell medicine- pharmacologically activating patients own adult stem cells—regen. med 
• stem cells involved for stem cell therapy

  • ES CELLS - PLURIPOTENT , MANY ADVANTAGES
  • iPS cells - SOLVE PROBLEMS OF TISSUE REJECTION
  • ADULT STEM CELLS - since embryonic stem cells are not allowed in some countries like Germany and Italy… this helps to substitute it with adult stem cells
• what is the first stem cell therapy ?

  • hematopoietic stem cell therapy
  • approved in 1980s
• Blood diseases

  • ex. leukemia, lymphoma, aplastic anemia
  • patients blood cells and immune systems are damage , have cancer cells
  • blood and immune cells need to be replaced for survival
  • ** stem cell therapy is needed : hematopoietic stem cell therapy
  • before treatment, immune system is destroyed by chemotherapy or irradiation.
  • then, donor is injected with cytokines to allow their HSCs to proliferate and circulate
  • donor HSCs are removed and implanted into the patient
• Parkinson's disease

  • good for stem cell therapy bc single cell type involved
  • what is it? degeneration of dopamine producing nerve cells
  • where? substantial nigra in brain which is in the midbrain
  • symptoms: loss of muscle control, tremors, stiffness
  • treatments:
  • L-dopa —> dopamine (regulating dose is hard)
  • deep brain stimulation - newer treatment… doesn't improve alls symptoms
• PD studies

  1. Fetal stem cells

  • isolated from fetus and implanted into patients brains
  • successful in rates, tried in humans but ethical issues
  • advantages: fetal stem cells are a good source of dopamine neurons, and no immune rxn
  • disadvantages: ethical concerns, aborted fetuses, availability scarce, only some studies are successful, tissue rejection, contamination with other neurons like serotonin
• PD studies

  • fetal, MSC, muse, es, ips
• pd studies

  b. MSCs (mesenchymal stem cells)

  • animal studies
  • can differentiate into dif cells
  • can differentiate into dopamine neurons (differentiating stem cell into right kind of linkage)
  • transplanted into rat models
  • some relief of symptoms

  c. Muse cells

  • see above, with MSC
  • as muse is a subset of MSC

  d. ES cells (Embryonic Stem Cells)

  • ES differentiated into dopamine (DA) neurons
  • implanted into brains of PD patient brains
• pd studies

  iPS cells (Induced Pluripotent Stem Cells) f. NSCs (Neural Stem Cells)

  • monkey models
  • iPS cells generated from fibroblasts from Parkinson's monkeys
  • differentiated into DA neurons
  • neurons transplanted back into monkeys (autologous= self ) or into other monkeys (allogenic=neighbor)
  • autologous result: improved movement, decreased signs of depression
• pd studies

  • human studies
  • IPS cells derived from parthenogenetic stem cells
  • cells transplanted into midbrains of PD patients.
  • goal : new cells will replace dead and dying cells . provide protection to that cells that remain
  • iNSC-DAP
  • NSCs derived from iPS cells that originally came from the patients' own peripheral blood mononuclear cells
  • cells transplanted into the brains of the same patients by injection (autologous treatment)
  • differentiated iPS cells
  • transplantation of these cells into brains of PD patients
• CHALLENGES FOR PARKINSON DISEASE STEM CELL STUDIES

  • getting stem cells to become functioning neurons
  • methods for delivering stem cells to right targets
  • learning how to get the stem cells to integrate into brain
• ALZHEIMER'S DISEASE

  • neurodegenerative disease
  • over time, certain nerves die
  • currently no cure
  • current drugs temporarily help with some symptoms
  • more complex bc multiple cell types are likely involved
  • most common cause of dementia
  • affects nerves of many parts of the brain
• ad challenges

  • challenges: work done in animal models

  1. Many parts of the brain are affected, so stem cells would have to travel to multiple areas of the brain
  2. B. Stem cells would have to differentiate into the many types of neurons.
  3. C. The new neurons would have to integrate and make the right connections.
  4. D. Even if the brain can integrate new neurons, can they do so after the Alzheimer’s has started?
  5. E. consider Would the new stem cells be damaged by the tau protein that is already in the brain of Alzheimer’s?
• ad

  • pts have abnormal build up of certain proteins in brain
  • amyloid beta
  • clumps together to form plaques and tau …twisted into protein tangles
  • these plaques prevent nerve cells from communicating properly ( role is still unclear)
  • tangles make it difficult for cells to get nutrients they need
• ad studies

  iPS cells

  • some but not all Alzheimers may have a genetic component (familial)
  • researches have developed iPS cells from skin cells of patients with familial Alzheimers
  • these cells differentiated into neurons and grown

  HSPC (subset of HSCs)

  • Hematopoietic Stem Cell Progenitor Cells
  • healthy HSC and HSPCs transplanted into mouse alz brain
  • symptoms reversed, neuroinflammation and amyloid decreased
• • C. Multiple Sclerosis (MS)
  • disease that affects CNS
  • lack of myelin
  • myelin insulates axons of nerves
  • oligodendrocytes produce myelin
  • the patient's immune system attacks myeline sheaths surrounding nerve fibers
  • leads to breakdown of transmission of nerve signals
  • symptoms: numbness, blindness, paralysis
  • treatments : immunosuppression …temporary only
• stem cell treatments for MS

  • Autologous adult hematopoietic bone marrow stem cells (HSCs)
  • pt immune cells destroyed
  • injected with their own HSCs
  • reinfection resets the body immune system
  • improvement of symptoms
  • MSCs
  • isolated from bone marrow or blow
  • grow in culture, amplify, back into pt
  • can lead to regeneration in damaged tissue
  • beneficial : immunosuppressive activity
  • PRODUCE NO
  • NO= suppresses T cell proliferation and suppress immune system
• D. AGE DEPENDENT MACULAR DEGENERATION (AMD)

  • CAUSED BY degeneration of macula (part of retina)
  • retina pigment epithelial cells are largely affected
  • no approved stem cell treatments
  • replacing retinal pigment epithelial cells (RPE) is being researched

  study: iPS cells

  • human studies
  • IPS cells isolated from blood
  • into eyes of AMD patients
• DAMAGE TO CORNEA

  • eye problem that can abolish reduce vision
  • caused by foreign objects, chemical exposure , too much sunlight, or genetic abnormalities
  • treatment:
  • corneal transplants - but not always avail
  • cant be done if limbus is abnormal or has been destroyed
• damage to cornea

  • limbus - zone of tissue that surrounds iris of eye
  • has corneal stem cells — needed for transplantation of donor cornea
  • limbal stem cells can be isolated from good eye, donor, or grown in culture
  • then, these cells placed around iris of damaged eye
  • once transplanted, they might be able tor generate the different layers that makeup the cornea

  LIMBAL STEM CELLS

  • isolated from good eye or donor
  • grown in culture to amplify
  • placed around the iris of the damaged eye
  • may regenerate dif layers that makeup the cornea
• F. SKIN DAMAGE AND BURNS

  • open wounds must be covered as quickly as possible to prevent fluid loss and infection
  • possible solutions:
  • saline baths - tho drawbacks
  • skin grafts - immune system often rejects
  • growing skin cells from patient and using them to make artificial skin by tissue engineering - slow process, need faster treatment
  • NEW: turn human iPS cells into artificial skin
  • provide stock of skin to use after genetic matching

  IPS cells

  • make them
  • differentiate them
  • make them into skin cells for pt to use after genetic matching
• G. ORGAN TRANSPLANTATION

  • sometimes the best option for certain disorders , but shortage of organs available
  • alternative: cell transplantation
  • relevant cell types transplanted into damaged organ to replace cells that dont work/dysfunctional
  • can be delivered directly to the place in body where they r needed like the heart, muscle, pancreas, or administered Intravenously through blood vessel
  • but in order for these cell based treatments to work, u need enough cells available
• organ transplant

  • but in order for these cell based treatments to work, u need enough cells available
  • growing stem cells and differentiating them along with the right lineage that u need — might help to achieve sufficient amount of cells
  • stem cells can also be modified with gene therapy to replace cells in case genetic abnormality
• organ transplant issues

  • ISSUES
  • BETTER for tissues that dont have too many cell types that must work together
  • ex. in the heart, (one cell type aka the heart muscle cell), dies bc of heart attack/MI.
  • so, u get new heart cells by differentiating pluripotent stem cells (can turn into anything) to replace the damaged cells
  • ex. multiple cell types damaged, more difficult to treat
• H. HIV

  • virus that causes AIDS
  • infects T cells
  • HIV virus uses a combo of receptors to enter the cell
  • CD4, CCR5
  • HSCs (hematopoietic stem cells) can be used to cure or prevent HIV AIDS
  • HIV POSITIVE, immune cell cancer patients got bone marrow transplants
  • small % were cured
  • bc donors had mutation in CCR5 gene on both copies
  • treatments
  • antivirals used

  umbilical cord stem cells

  • stem cells donated from umbilical cord blood
  • cured of HIV if donor had a mutation in both copies of ccr5 gene
• . HEART FAILURE

  • heart doesn't pump as well as it should
  • . slide 66
  • body doesn't get as much oxygen
  • leads to organ damage and death
  • no cure, but heart transplant rare
  • inflammation is key factor of heart failure
  • if inflammation persists, can lead to blood vessel plaques, blood clots, heart attacks, strokes

  MSCs

  • secrete anti inflammatories
  • goal for treatment : reduce inflammation
  • cells injected into myocardium (heart muscle)
  • pt showed reduction in heart attack
• K. OSTEOARTHRITIS

  • chronic joint disease

  MSC

  • can differentiate into chondrocytes and can modulate immune system
  • intra articular injection
  • differentiate in vivo after injection
  • differentiate into various cells needed
  • goal: MSCs will differentiate into various cell types such as chondrocytes, adipocytes, osteocytes (bone), and in turn secrete factors that are necessary for healing and maintaining the joint
• L. COVID19 AND ARDS

  • . acute respiratory distress syndrome
  • covid can lead to severe inflammation which leads to ARDS
  • high mortality rate
  • activation of immune cells, release of pro-inflammatory cytokines, damage to lungs

  MSCS

  • can migrate to lungs
  • release anti-inflame factors
  • MSCs are safe, they are ‘immune privileged’, immunomodulatory, antimicrobial, and regenerative. They can migrate to the lungs and release anti- inflammatory factors thus reducing inflammation. MSCs may therefore have the potential to increase survival due to ARDS.
• G. fertility

  • development of baby mice from 2 male mice using mouse stem cells
  • skin cells from male mouse tail made into mESCs
  • these cells treated with reversin, a small molecule, which eliminates the Y chromosome and duplicates the X chromosome
  • dna injected into denucleated egg cell
  • egg cell made into haploid, fertilized by sperm by other male
  • egg —> blastocyst —> inserted into surrogate female mouse
  • progeny had dna of both male mice
• GOOD SOURCES OF ADULT STEM CELLS

  1. ADIPOSE DERIVED STEM CELLS
  2. stem cell found in fat tissue
  3. significantly easier to isolate the other adult stem cells like HSC and MSC
  4. can be used in regenerative med
  5. repair bone or fat tissue
• STEM CELL CHALLENGES

  • Not all stem cells are the same
  • need to prove stem cells are pluripotent
  • need more reliable markers to assess
  • find ways to get stem cells to differentiate into desired cell type
  • possible rejection by hosts immune system
• dealing with problems

  • identify best sources of adult stem cells
  • use autologous stem cell therapy to avoid rejection
  • use of IPS cells to avoid immune system rejection
  • creation of banks of dif stem cells so that patients can access best possible genetic match