personalized treatment of diseases using cellular treatment

what is stem cell medicine?

• broad field of medicine that involves the use of stem cells or stem cell biology to treat disorders includes:

• stem cell therapy: treating the patient by transplanting new stem cells itnto the body

• activation of endogenous stem cells: pharmacologically activating the patients' own adult stem cells to promote repair (a type of regenerative medicine)

what are the types of stem cells that may be promising for stem cell therapy?

ES cells, adult stem cells, iPS cells

why are ES cells promising for stem cell therapy?

• pluripotency is a major advantage: can become almost any cell type
• advantage: high flexibility
• limitation: ethical + safety concerns

why are adult stem cells promising for stem cell therapy?

• multipotent: limited differentiation
• advantages: fewer ethical concerns and lower immune rejection, especially if autologous (from the same patient)
• e.g. HSCs used for bone marrow transplants

why are induced pluripotent stem cells promising for stem cell therapy?

• reduce ethical concerns
• may allow autologous therapies
• safety issues are still under investigation
• adult cells reprogrammed to a pluripotent state

what are the stem cell therapies FDA-approved and in routine clinical use?

• hematopoietic stem cell transplantation: bone marrow, peripheral blood, and cord blood
• used for leukemia, lymphoma, bone marrow failure syndromes (BMF), and certain genetic blood disorders

what are the cell therapies in clinical trials?

• most ongoing stem cell trials use adult cells, including HSCs and MSCs
• many trials target non-hematologic diseases (e.g. heart diesases, diabetes, spinal cord injury, MS, epilepsy): many are in early clinical phases (phase I/II), but some have advanced to later stages

what are the major challenges of stem cell therapy?

1. insufficient regulation

• some treatments are not FDA-approved but still marketed

1. insufficient education

• patients may have unrealistic expectations
• literature about stem cells may be confusing
• it may be unclear what kinds of stem cells are used for research studies that patients see

1. technical challenges

• difficult to isolate cells, grow cells, differentiate cells properly, and get cells to integrate properly
• undifferentiated cells may form TUMORS

1. immune rejection

• body may attack transplanted cells
• autologous therapy helps but not always possible

1. side effects

• risk of tumor formation
• other unknown long-term effects

what is the most established use of stem cells?

blood disorders

what are hematopoietic stem cell transplants?

• destroy diseases bone marrow (cancer, leukemia, other blood disorders)
• transplant healthy stem cells
• cells rebuild blood and immune system
• goal: replace defective cells
• has been used for decades

what is parkinson's disease?

• loss of dopamine-producing neurones (specifically A9 DA neurons)
• leads to tremors, stiffness, loss of movement control
• stem cell goal: replace lost dopamine neurons by using stem cells

what are the current treatments for PD?

• L-DOPA to replace dopamine: helps for a while but does not stop neuron loss
• deep brain stimulation (DBS)

what are the requirements for stem cell treatments for PD?

new cells must:

• differentiate into the correct neuron type
• be delivered to the correct brain region
• be capable of long-term survival
• not form tumors

what studies were done in animals?

• iPS cells were generated from fibroblasts from monkey models of PD
• the cells were differentiated into dopamine neurons
• these neurons were transplanted back into the monkeys (autlogous) or into other PD monkeys (allogenic)
• autologous recipients showed improved movement and decreased signs of depression

what is alzheimer's disease?

• neurodegenerative affecting many brain areas
• protein buildup: amyloid plauqes, tau tangles
• no cure
• stem cell therapy is still experimental

what are the challenges to AD?

• many cell types affected, unlike PD, where one specific cell type is affected
• need correct integration of cells in brain
• disease environment might damage new cells

what is multiple sclerosis?

• immune system attacks myelin: normally produced by oligodendrocytes and insulates nerves
• symptoms: can include symptoms such as weakness, numbness, paralysis, congitive issues

what are the stem cell strategies for MS?

• immune reset using HSCs (most promising)
• immunomodulation using MDCs
• remyelination (still under investigation)

what is immune reset using HSCs?

• usees autologous hematopoietic stem cell transplant (HSCT)
• goal: reset the immune system
• currently being used in specialized centers for aggressive MS, but does not yet have specific FDA approval for MS

what is the process of immune reset using HSCs?

1. harvest the patient's own HSCs
2. use high-dose chemotherapy to eliminate autoreactive immune cells: cells that destroy the patient's own myelin
3. reinfuse the patient with their own stem cells
4. the immune system regenerates, and this somehow resets the immune system
5. this does NOT repair myelin directly, but it reduces autoimmune attack and has been successful for some patients

what is immunomodulation using MSCs?

• MSCs are sourced from the patient's bone marrow or adipose tissue
• MSCs do not replace oligodendrocytes, but they have been shown to reduce the immune system and inhibit inflammation
• this is due to paracrine signaling, where the MSCs are thought to secrete signals that reduce T cell activation and production of inflammatory cytokines
• results have been mixed
• this method is under investigation, but the HSCT method so far appears to be more promising (stronger clinical evidence)

what is remyelination?

• use iPS cells derived from skin cells to replace damaged oligodendrocytes
• still in early preclinical stages

what is macular degeneration (AMD)?

damage to the retina: specifically, damage to the retinal pigment epithelial (RPE) cells

what is the stem cell approach for treatment of MAD?

• use stem cells to replace RPE cells, inject these cells into the retina
• these cells can come from iPS cells that are differentiated into RPE cells
• protocols have been developed to differentiate E cells into RPE cells for treatment
• another study used patient-derived iPS cells that were differentiated into RPE and transplanted into the retina
• these studies are in experimental stages or in clinical trials

what is corneal damage?

• stem cell treatment is under investigation
• a type of stem cell treatment under investigation for corneal damage involves the limbus and limbal stem cells

what is the stem cell approach for treatment of corneal damage?

• limbus zone: zone of tissue that surrounds the iris
• limbal stem cells can be isolated from the good eye or from a donor and added to the iris of the affected eye
• once transplanted, these cells may have the ability to regenerate the different layers that make up the cornea
• these types of studies are still in preclinical studies, in some cases, in clinical trials

what are some ides for using stem cells to repair damaged skin?

• grow the patient's skin cells in the lab
• use them to create artificial skin
• iPS cells may be a better new option and can be used to create artificial skin
• banking iPS cells may allow patients to have a strong genetic match

what are the problems and solutions of organ transplantation?

• problem: not enough donor organs solution:
• replace specific cells instead of the whole organ
• these stem cells would be differentiated before being used
• stem cells may repair tissues and in some cases, can be genetically modified to correct genetic abnormalities

how does the HIV virus work?

• HIV is the virus that causes AIDs
• uses a combination of a receptor (CD4) and coreceptor (usually CCR5) to enter the cell

can stem cells prevent AIDs?

• some patients who had HIV, AIDs were unexpectedly cured after stem cell transplants that were done for reasons unrelated to the HIV AIDs
• this result was due to genetic mutation in the CCR5 gene of the donor cells, thereby blocking viral entry
• this shows potential for future therapies

what is heart failure?

• a condition where the heart cannot pump effectively
• the DREAM-HF trial involved the use of MSCs
• MSCs from donors were injected into heart muscle (myocardium) of patients
• MSCs may reduce inflammation and improve outcomes
• results were promising but not perfect, more testing is needed

what is osteoarthritis?

• joint degeneration
• MSCs may be promising for treatment
• MSCs may develop into chondrocytes and reduce inflammation
• still in experimental stages or clinical trials