Diabetes Cure Final Mona Samahy

8/14/2019 Diabetes Cure Final Mona Samahy

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Diabetes Mellitus (DM)

A group of metabolic diseases characterized byhyperglycemia, resulting from defects in insulinsecretion, action or both.

The chronic hyperglycemia of diabetes is associated withlong-term damage, dysfunction and failure of variousorgans, especially the eyes, kidneys, nerves, heart andblood vessels.

It is the most common endocrine metabolic disorder of childhood and adolescence.


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Etio lo gy and Patho genes is


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Pathogenesis of type 1 diabetes


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The clinical and biological characteristics of different subtypes of type 1 diabetes

Type 1a Type 1b Type 1c

Signs of anti-isletautoimmunity

+ - -

Duration of symptomsBefore diagnosis

8 months 7 months < 1 week

Ketosis, ketoacidosisat diagnosis

frequent frequent constant

Blood glucose levels

at diagnosis

HbAlc at diagnosis Normal orslightly elevated


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The war on Diabetes Mellitus


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The war on DM

Starts by attempts to identify environmentaldeterminants of DM in the young whichfocus to identify dietary , infectious , and

other environmental tr iggers of type 1a DMin genetically at risk chi ldren .

Identification of such triggers could lead to thestudy and implementation of primary prevention.


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Through

1- Pr imary Prevention

Avoidance of dietary

offender

Immunization against an

infectious trigger


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TRIGR STUDY

The trial to reduce IDDM in thegenetically at risk is ongoing.

Its focus is to determine whether delayedexposure to or avoidance of certainfood proteins will reduce the risk of

developing type 1 DM in infants atGenetic Risk.


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Type 1a DM is the autoimmune form whose major geneticrisk traits are defined on certain HLA DR/DQ alleles.

The genes mutation will not be correctable by avoidance of dietary or infectious agents.

However, insights gained from these mutations may

facilitate ultimate prevention strategies such asimmunization with specific segments or epitopes of theinsulin molecule to limit autoimmune self aggression.

The results of primary prevention trials are still unknown(June, 2008)


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Even if these studies identify one or severalmagic bullets for arresting or preventing theprogression of DM, we would still be

confronted with the problem of cu r ing or revers ing established disease.

2- Secondary Prevention


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Insulin has been the gold standardtherapy for DM since its discovery.

It remains the only pharmacologictherapy for type 1DM


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Before insulin wasdiscovered in 1921,everyone with type

1 diabetes diedwithin weeks to years of its onset

Before Insulin.Whats After?

JL on 12/15/22 and 2 mos later


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Insulin Therapy in Type 1 Diabetesis a must


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Ideal Insulin Regimens Type 1 DM

Minimizes nocturnal

hypos OptimizeFBS

Minimizes late morning andafternoon hypos

Basal -Bo lus Regim en

The challenge is to

Com e as c lose as pos s ib le to norm oglyc emia and reduce hyp oglyc emia .


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Although molecularly producedinsulin administered 4 or 5 times perday can provide a physiologic

regulation, yet it is not able to preventdiabetic complications that account forthe morbidity and mortality of diabetic

patients.


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Also insulin does not eliminate thetype1 DM hallmark : BETA- CELLSPECIFIC AUTOIMMUNITY.

In other words

Insulin is not a cure


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1. Either replace or maintain the functionalintegrity of the natural insulin-producing tissue.

2. Must at least control the autoimmunityor eliminate it altogether.

3. Easy to apply to a large number of patients

A successful cure must meet

the following criteria:


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Criter ion 1

Has been partially realized by allogenic islettransplantation.


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Development of Insulin-Secreting Pancreatic-Like Cells FromMouse Embryonic Stem Cells.


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Criter ion 2

Has been partially realized usingmonoclonal antibodies specific for T-cell

surface proteins.

Criter ion 3

Has yet to be realized


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New Approach to (fulfill the 3 criteria)


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A non-insulin based therapy,

With a focus on

Cell-Based Immunomodulation

Hoping for cure


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All proposals of treatment in thepast and recently are depending on

discoveries in understanding theimmune pathophysiology of

destruction of pancreatic cells that

results in DM.


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Nature of autoimmunity in type 1a DM

The major affectors of -cell destructionare T cells reactive to -cell-specificantigens.

A strong genetic predisposition is the keyfor genetic susceptibility loci thataffect genesis, function and survival of

immune cell subsets including T cells anddendritic cells.

Type 1 Diabetes as immune destruction of beta


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APC

T-cellT-cell

B-cell

Inflammatorycell

Cytokines

Beta celldeath

Type 1diabetes

Antibodies

CytotoxicT-cell Beta cell

Beta cellantigens Fas

(IL1, TNF , NO)

Th1 (IL2, IFN )

(ICA, IAA, IA2, GAD65)

Type 1 Diabetes as immune destruction of betacells


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The epitope spreading phenomenon i.e.expansion of newly recognized antigens

observed in the islet inflammation is due to:

Islet-reactive T cellsthat were generatedin the thymus early

in ontogeny

Generation and survivalof T cells activated inthe periphery by these

new antigens


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There is a pathologic vicious circle of continuouspresentation of old and new antigens, collected by the

dendritic cells (DC) from the newly destroyed -cells tonaive T cells in the pancreatic lymph nodes eventually

go back to the pancreas to kill other -cells.

This vicious circle does not allow the recovery of theinsulin secreting cells, even when the physiologic

homeostasis process tries to substitute the lost cellswith new cells.


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Therefore, an approach developed to stop

autoimmunity in already diabetic patients,could possibly facilitate the recovery of

autologous insulin production.

So , safe induction of an autoimmunity freestatus might became a new promising

therapy for type 1a DM.


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In the past 20 years, researches have mademany promises to cure type 1 DM. Only

recently it has been possible to clinicallyimplement a limited number of successes.


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Autologous transplantation of hematopoietic stem cellenriched BM was used to treat type 1 DM.

The effects were limited to simple postponement of DM recurrence, i.e.: just delayed by the timenecessary for the transplanted BM to reorganize

itself and to reestablish all of its immunocompetentcell subpopulations.

Autologous Bone Marrow Transplantation.


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The autologous BM did not change the patient'sgenetic characteristics under which tolerance forthe insulin producing beta cells was not achievedin the first place.

So , Autoimmunity easily recurred.

Autologous Bone Marrow Transplantation.

BMT can encourage


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gbeta cell regeneration

Regeneration of beta cellsin diabetic NOD mice

A) Infiltration of T cells destroys beta cells

B) After BMT infusion, signs of autoimmune destructiondiminish

C) Insulin-producing cells start toappear (red)

D) 4 mo after BMT infusion, seeproliferation of insulin-producingcells (red)


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Another approach was developed to modify the genetic characteristics of apatient BM-derived stem cells in vitrowhich will result in T-cells or (APC) thatcannot initiate an autoimmune response.(maybe transferable to clinical trials in the nearfuture)


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This was achieved by:

Transduction of BM-derived stem cells withprotective (non diabetogenic) HLA transgenes.

Infusion of the engineered cells will culminate inrepopulation of the thymus with protectiveHLA-expressing APCs.

This in turn will decrease the probability that T cells with diabetogenic T cell receptors matureand exit into the periphery.


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It is postulated that the Rest per iod from the

autoimmune destructive process permitsregeneration of endogenous cells frompancreatic stem cells within the pancreaticducts or islets.

The suppression of the immune environmentby several means was conclusively shown

to be the mechanism that resulted inrecovery from type 1a DM in NOD mouse.


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Two novel recent mechanisms involvingcell based immunomodulation aimed at

producing a cure for type 1a DM :

1. Diabetes-suppressive autologous DC.

2. Diabetes-suppressive microsphere vaccine


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1. Diabetes-suppressive autologous DC.

The first clinically adapted immunoregulatorycell therapeutic


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Why dendr i tic cel ls?

DC are the body's sentinels largelyresponsible for host surveillance againstmicro-environmental anomaliesincluding pathogen invasion, infection,and damaged tissue architecture, while

coordinating the mechanisms of self

tolerance.


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DC continously traffic throughout all bodytissues sampling molecules from their

surroundings, where it is believed theymaintain potentially autoreactiveimmune cells in quiescence eitherdirectly or via indirect regulatory

immune cell networks.

Why dendr i tic cel ls?

When DC encounter local disruption of tissue


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archi tectur e & elevated proinf lammatory signal f rom infected cel ls:

Undergo maturationthrough a series of internal changes.

Migrate away from thesite of danger and into

the closest LNs.

Within the LNs, the DC, as a powerful APC,initially interacts using its class I or class IIMHC / peptide complex with the TCR present on a nave T cell. This will constitutethe so-called f irst signal for T-cell activation.


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To bring a T cell to full activation, asubsequent contact between receptors on bothAPC & T cell (Co receptors) is necessary.

Co-stimulatory molecules present on the APCwith their counterparts on the T cell interactto further stabilize the signal of activationbetween the two cells, thus providing

the second signal.


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Absence of this co-stimulatory molecule binding

and consequently lack of secondary signalgeneration has been shown to lead toimpaired activation of the responding T cell,eventually bring it to functional anergy or apoptosis .

This is indeed the outcome of many

immunosuppressive strategies aimed at co-stimulation blockade.


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Many investigations support the concept that

functionally immature DC (characterized bylow to absent co-stimulation) lead to Immune hyporesponsiveness .

Exogenous administration of functionallyimmature DC achieves long term and stable allograft survival in a variety of mouse andrat models and prevents a number of autoimmune diseases.


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Recently

I n vitro administration of nuclear factor-kappa (NFB) decays to DC as well as directtargeting of CD40, CD80 and CD86 withantisense oligodeoxyribonucleotides (AS-ODN) reduces co-stimulatory molecule levelsproducing functionally immature DC capable

of preventing or reversing new-onset DM in theNOD mouse.


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Numerous clinical trials have safelyused DC-based treatments forcancer therapy providing the basisfor clinical adaptation of DCadministration for Type 1aDM ttt.


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These DC which express low levels of CD40, CD80 andCD86 are injected into the patient by ID route at ananatomical site proximal to the pancreas.

DC will migrate to the nearest LNs where they will startto interrupt the vicious circle that maintains islet-specific inflammation i.e., insulitis.

This therapeutic approach should be more successful

when DC injections start close to the clinical onset of DM.


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I N TH E PANCREAS

DC acquire -cell specific antigens fromapoptotic cells, leading to the eventual displayof these antigens to T cells in the pancreas-

draining LNs. The lack of co-stimulatory molecules will result in

anergizing signal to the T cells, and interruptthe T cell mediated anti-beta-cell epitopespreading phenomenon.


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The cessation of the autoimmune diabetogenic insultshould be sufficient to:

Promote rescue of still present insulin producing cells and/or

Promote neogenesis of other insulin producingcells in the pancreas, even after the disease onset.

This tri al is underway at (6/2008) & once safety hasbeen demonstrated, a phase I I efficacy trialwill start, involving new onset diabetic patients.


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2. Diabetes Suppressive microspherevaccine

Diabetes Suppressive microsphere vaccine


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Diabetes Suppressive microsphere vaccine

In spite of the promise of the previous study,many cumbersome logistical requirements togenerate these diabetes-suppressive DC have

been encountered.

This may limit the future enrollment of new onsetdiabetic children in the efficacy phase of thetrial.


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Difficulties:

Leukopheresis takes 2 or 3 hours to provide sufficientprecursors cells to generate the number of DCnecessary for six to eight injections.

The obtained DC should be exposed to AS-ODN in GMPfacilities in which the laboratory practices arefrequently difficult to reproduce. GMP facilities arefrequently located far away from the clinic where thepatients are treated.

Many DC are lost during the freezing/thawing procedures.


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In an effort to avoid these steps, an alternativemethod to stabilize DC immaturity directlyin vivo using microparticle carriers of

immunomodulating agents like AS-ODN(microsphere delivery system) have beendone.


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This microparticle carriers (microspheredelivery system) is directed against 3 keycostimulatory molecules:

CD40CD80

CD86

Essential for normal immune response


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This microsphere delivery system in

which AS-ODN have beenincorporated, is named Baxter H ealthcare' s PROM AXX .

The inert PROMAXX microspheretechnology has been shown to besafe and effective in human trials.


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More importantly, when administeredin vivo, this technology is neutralwith respect to DC maturation

state compared with the knownimmunostimulatory properties of other microsphere formulations.


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Other polyplex formulations have an inherent

capacity to induce the upregulation of co-stimulatory proteins at the DC surface,whereas the PROMAXX technology doesnot.

This neutrality on DC maturation is a criticalcriterion in adopting microsphere chemistryfor immunosuppressive objectives where DCare involved as mediators.


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They predict that once all preclinical studiesare completed, a phase I/II trial can beinitiated.

The microspheres are simple to manufactureto clinical grade on a large scale and donot involve the cumbersome logistics for

DC based therapy.


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This novel microsphereformulation represents the f ir st

diabetes suppressive and reversing nucleic acid vaccine that confers an

immunoregulatory phenotype toendogenous DC.

H l i i l


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How long is a single courseof microsphere particleseffective?

Does response wane withrepeated injection?

These questions remain to be answered.

But, if it's effective NEW ERA intreating type 1 DM will appear.

The light at the end


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The light at the end

of the tunnel for

Diabetes Cure


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Diabetes Cure Final Mona Samahy

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