lec 26 - personalized treatment of disease (minden)

potential uses for stem cells in disease treatment

• parkinsons

• alzheimers

• multiple sclerosis (MS)

• amyotrophic lateral sclerosis (ALS)

• spinal cord injury

• diabetes

• cardiomyopathy

• liver failure

• regenerative medicine

• macular degeneration

• cornea disorder

• burns and skin disorders

most treatment involving stem cells are still in clinical trials

• mostly HSCs

current status of stem cell treatments

• majority of clinical trials at the current time involve the use of adult stem cells, esp. HSCs

• many of these are designed for the treatment of non-blood diseases such as heart disease, diabetes, spinal cord injury, MS, epilepsy

• many studies are still in early phases

• some are farther along, such as those involving heart disease

• in the case of heart disease, certain trials have shown that the procedures are safe and now they can be applied to larger groups of pts

• only FDA approved stem cell treatments at this time are with adult HSCs

challenges and problems with stem cell treatments

while there are potential new stem cell treatments on the horizon, many challenges, leading to unrealized expectations and false promises

• insufficient regulation

• insufficient education of pts → leads to unrealistic hope

• technical challenges with using stem cells

• dealing with possible rejection by immune system

• possible side effects including cancer

technical challenges: stem cell differentiation

• in order to use stem cells in disease treatment, important to start the differentiation process in vitro before introducing cells into patients

• stem cell researchers need to develop methods for differentiating cells along different lineages

• making cells differentiate into the cells of the ectoderm tissue (such as nerve cells) has been the most straightforward followed by mesoderm (such as heart and vascular cells)

• endoderm tissue (such as lung and pancreas cells) = most difficult

• implantation often has opposite pattern

  • for example, implanting cells into the pancreas can be easier than transplanting nerve tissue into the nervous system

road to the clinic

most studies go thru the following steps

1. basic research

   • studying the cells in the lab

   • using various models

   • including cell cultures and animals

2. preclinical research

   • testing the safety and efficiency of the new potential therapy using non-human models, including various animals

3. clinical trials

   1. phase I → test the therapy on small group of people with the goal of assessing the safety of the treatment

   2. phase II → give the therapy to a larger group of patients to test efficacy and to test safety in more depth

   3. phase III → treatment is given to larger group of individuals to tests its efficacy; results are compared with other treatments/trials; only if this stage successful will the drug go on the market

   4. phase IV → occurs after the drug is on the market to further asses risks and the best ways to use the treatment

stem cell medicine vs stem cell therapy

• stem cell therapy = treating the patient with NEW stem cells

• stem cell medicine = may involve pharmacologically activating the pts’ own adult stem cells such as in some cases of regenerative medicine

which type of stem cells to use for stem cell therapy

• ES cells → pluripotent; many advantages

• iPS cells → may in the future solve problems of tissue rejection

• adult stem cells → countries in which Es cells are banned; have been helpful in paving the way for studying disease treatment with adult stem cells

some diseases and conditions for which stem cell therapy may hold promise

• blood disorders, leukemia, aplastic anemia → HSC therapy

parkinson’s disease and stem cell therapy

• one of the early diseases for which stem cell therapy has been studied

• good candidate for stem cell therapy b/c a single cell type is involved

• different approaches have been studied, involving different types of stem cells

• good model for understanding stem cell treatment b/c different types of stem cells have been proposed or studied for treating the disease

what is parkinson’s

• degeneration of dopamine producing nerve cells in the substantia nigra

• loss of muscle control, tremors, stiffness

treatment for parkinson’s

• traditional methods rely on the use of L-dopa

  • L-dopa is converted to dopamine

  • can be effective for a while but regulating the dose is difficult

• deep brain stimulation = newer treatment but does NOT improve all symptoms and results vary among different patients

• newer methods that have been proposed involve the use of stem cells; some preclinical/clinical studies have been carried out

types of stem cells that hold promise for parkinson’s

• fetal stem cells

• MSCs

• muse cells

• ES cells

• iPS cells

• NSCs

parkinsons’s: fetal stem cells

• some of the earliest studies

• success was mixed

• advantages

  • fetal cells have strong capacity for proliferation and differentiation

  • fetal cells often do NOT induce an immune reaction

• disadvantages

  • ethical concerns, moratoriums (temp. ban), use of aborted fetuses, informed consent issues

  • availability of fetal stem cells; can be scarce, even within the fetus

  • results have been mixed, only some studies have been succesful

  • tissue rejection

  • contamination with other neurons, including serotonin neurons

parkinsons’s: MSCs

• MSCs can differentiate into several cell types

• several protocols have been developed to differentiate MSCs into dopamine neurons

• these differentiated MSCs have been transplanted into rat models of PD

• results = relief of some symptoms

• some researches also interested in using MUSE cells (subset of MSCs) to treat PD due to several advantages these cells may have over MSCs

PD: iPS cells

• iPS cells were generated from fibroblasts from the PD monkeys → cells were differentiated into DA neurons

• neurons were transplanted ack into the monkeys (autologous) or into other monkeys (allogenic)

• autologous recipient showed improved movement and decreased signs of depression

PD: iPS/NSCs

• clinical trial that involved the use of a type of NSCs

  • NSCs that were developed from iPS cells that originally came from the patients peripheral blood mononuclear cells

  • transplanted into the brains of the same pts by injection (autologous treatment)

  • pts will be followed for at least 3 years

• some clinical trials that have also been started involve ES cell line

challenges for using stem cell studies in PD

• getting stem cells to become functioning neurons

• methods for delivering the stem cells to the right targets

• learning how to get the stem cells to integrate into the brain

• importance of collaborative research

alzheimers disease

• more complex than PD b/c multiple cell types are most likely involved

• most common cause of dementia

• complex disease that affects the nerves of many parts of the brain

• makes effective treatment challenging

• precise cause of the disease = unknown

• people with alzheimers have an abnormal build up of certain proteins in the brain

  • include amyloid beta which clumps together to form “plaques” and tau which gets twisted into protein “tangles”

• one theory is that the plaque prevents nerve cells from communicating properly while tangles make it difficult for the cells to get the nutrients they need

• role for these plaques = unclear as recent studies show that they might NOT be as important as previously thought in the disease

more about alzheimers

• neurodegenerative disease

• over time, certain nerves die

• NO cure for alzheimers

• certain drugs can temporarily help with some of the symptoms but there are NO drugs that prevent or delay the loss of neurons

stem cells and alzheimers

stem cell therapy = active area of research with much of the work being done in animal models

• challenges

  • many parts of the brain are affected so stem cells would have to travel to multiple areas of the brain

  • stem cells would have to differentiate into many types of neurons

  • new neurons would have to integrate and make the right connections

  • even if the brain can integrate new neurons, can they do so after the alzheimers has started?

  • would the new stem cells be damaged by the tau protein that already in the brain of alzheimers?

alzheimers: iPS cells

in vitro studies using iPS cells

• some but NOT all cases of alzheimers may have a genetic component (familial)

• researchers have developed iPS cells from skin cells of patients thought to have familial alzheimers

• these iPS cells were differentiated into neurons and grown in culture

• in some cases these lab-grown neurons released beta amyloid protein

• this can give scientists a tool for studying the disease in vitro and testing drugs

alzheimers: HPCS cells (subset of HSCs)

• hematopoietic stem cell progenitor cells (HPCS) = slightly more differentiated form of HSCs

• healthy HSCs and HSPCs were transplated into the brain of an AD mouse model

• symptoms of AD were reversed, including memory and cognition problems; neuroinflammation was and beta-amyloid buildup was reduced

multiple sclerosis (MS)

• MS affects the CNS

• part of family of diseases the involve the lack of myelin

• myelin insulates the axons of nerves

• oligodendrocytes = cells that produce myelin

• patients’ immune system attacks the myelin sheaths surrounding nerve fibers → leads to breakdown in the transmission of nerve signals

• symptoms can range from numbness to blindness and paralysis

• current treatments often involve immunosuppression

• treatment = effective but usually temporary

MS: hematopoietic stem cell transplant (HSCT)

• autologous hematopoietic stem cell transplant (HSCT) clinical trial for MS

• in this trial, patients bone marrow stem cells (HSCs) are harvested

• patients immune cells are intentionally destroyed

• patients are then injected with their own HSCs

• re-injection apparently ‘resets’ the bodies immune system

• high percentage of patients who did NOT respond well to traditional therapies had significant improvement of symptoms

• though promising, NO approved HSCT treatments yet in the US but some patients are receiving this treatment as part of ongoing clinical trials

MS: HSCT process

1. administer pre-treatment to release blood stem cells from bone marrow into bloodstream

2. collect the blood stem cells from the bloodstream

3. freeze the blood stem cells in the laboratory until they are required

4. administer chemotherapy to remove or partially remove the immune system

5. return thawed blood stem cells by infusion into the vein

6. provide supportive medical treatment for at least 4 weeks as the immune system rebuilds

MS: other possible stem cell sources for treating MS

• adult MSCs are being tested in clinical trials

  • patients MSCs are isolated from bone marrow or blood and multiplied then re-introduced into patients in higher numbers

• iPS cells

  • take the patients skin cells and make them into precursors of oligodendrocytes

  • goal would be to re-introduce these into patients to restore the damaged oligodendrocytes

MS: MSCs

• iPS cells can lead to tissue regeneration in damaged tissue but another additional reason that MSCs may be beneficial for MS is that they have immunosuppressive activity

• mechanism by which MSCs have immunosuppressive properties is NOT entirely understood but seems to involve a combination of nitric oxide (NO) production and chemokine secretion

• MSCs produce NO

  • NO known to suppress T cell proliferation → suppress the immune system

good sources of adult stem cells

• scientists who work with adult stem cells are always interested in identifying the tissues that are the best possible source of adult stem cells

  • adipose derived stem cells (ASCs)

ASCs

• origin of ASCs = unknown

• methods for obtaining and using ASCs

  • fat tissue is collected

  • ASCs isolated from fat

  • ASCs expanded: self replicated in lab to produce more cells

  • ASCs guided to differentiate into different cell types

    • osteogenic

    • chondrogenic

    • adipogenic

potential uses for ASCs

regenerative medicine

• lipoaspiration to harvest ASCs

• 2 pathways

  • osteogenesis (bone formation)

    • ASCs are exposed to osteo-inductive factors → differentiate into bone cells → used for skeletal reconstruction

  • adipogenesis (fat formation)

    • ASCs are exposed to adipogenic induction factors → differentiate into fat cells → breast/face reconstruction