the great story of gene therapy

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ReferencesGene Therapy Industry Report 2021. Labiotech. June 2021.Jef Akst. Targeting DNA. The Scientist. | Lucy Reading-Ikkanda. Delivering New Genes. June 2012.Ansar Karimian et al. CRISPR/Cas9 technology as a potent molecular tool for gene therapy. Journal of cellular Physiology. January 2019.

Significant Advancements

over the last decadeScene 1

1989First approved protocol to use gene transfer into humans

2003The complete sequence of the human genome is identified

2009Intensive research to increase vector safety

2016First ex-vivo gene therapy approved

2019First gene therapies approved for the treatment of SMA (Zolgensma) and β-thalassemia (Zynteglo)

1972Gene Therapy concept is discovered by Friedmann and Robin

2008First adenovirus gene therapy complete phase III clinical trial

2012First gene therapy approved in Europe

2017First gene therapy approved in the USA

1990First clinical trial to deliver a therapeutic gene is achieved

in the USA

Sensitivity Robustness Sample availability

Selectivity Sample stability

Challenges

Oncology

>1400 >400

Neurological Disorders

>300

Genetic Disorders

>350

Others

Therapeutic areas

ApproachesReplacing

A mutated gene

InactivatingA mutated gene

IntroducingA new gene

> 2400Product

candidates

>1350Preclinical

>300Phase I

>250Phase II

>50Phase III

20 approved

gene therapies

ApproachesReplacing

A mutated gene

InactivatingA mutated gene

IntroducingA new gene

Long TermSafety

EfficacyOver Time

NeutralizingImmune

Responses

ManufacturingScale Up

EvolvingRegulatoryGuidance

Challenges

Oncology

>1400 >400

Neurological Disorders

>300

Genetic Disorders

>350

Others

Therapeutic areas

Adenovirus20%

Retrovirus18%

Plasmid DNA17%

*Adeno-associated virus

AAV*8%

Lentivirus7%

Others

VectorsAdenovirus

20%

Retrovirus18%

Plasmid DNA17%

*Adeno-associated virus

AAV*8%

Lentivirus7%

Others

Vectors

Scene 2

Major Key facts

in Gene Therapies

Cell with amutated gene Production of a

mutated proteinDiseases

Gene Therapy can correct these mutations

How does gene therapy

work ?Scene 3

By using CRISPR/CAS9

8,659

Mutated cell Identification of themutation responsible

for the diseaseCreation of a strand of guide RNA

that matches the mutated DNA sequence

Cas9 cuts, nicks or targets the affected sequence The Guide RNA identifies the mutated DNA

Guide RNA

Cas9

Addition ofTarget gene

DNA

 Non-HomologousEnd-Joining

Gene knockoutPrime editingBase substitution

Adenine/Cytosine

base editorRT enzyme

Gene replacement Gene repair Gene silence

NONINTEGRATING VIRUSES INTEGRATING VIRUSES ONCOLYTIC VIRUSESNONINTEGRATING VIRUSES INTEGRATING VIRUSES ONCOLYTIC VIRUSES

By using Viral Vectors

The great story ofGene Therapy

Virus entersin the cell

Conversioninto DNA

Functionalprotein

expressed

DNA isintegrated into nuclear

genome

Adeno-associated virus(AAV)

Therapeutic DNA

Therapeutic DNA

Oncolytic virus

Lentivirus

TherapeuticRNA

Virus entersin the cell

Endosomebreaks down

Functionalprotein

expressedVirus bindsto the cellnucleus

Virus preferentiallyinfects tumor cells

Virus replicatewithin the cell

Tumor Lysis

IN VIVO

EX VIVO