Stem cell therapy

Prof. Graziella Pellegrini

University of Modena

Holostem Terapie Avanzate

May 26-28 2016

Centre for Regenerative MedicineUniversity of Modena and Reggio Emilia

The potency of cells

How many stem cell types can be used?

Embryonic IPS(Inducedluripotent

Stem cells):Adult cells genetically manipulated to

become embryonic-like

Adult

The importance of regenerative medicine field

• Regenerative medicine treatments were mainly proposed

for rare diseases

• Regenerative medicine allows studies

- on drug targets or

- to target personalized drugs

Therefore

Regenerative Medicine, when carefully controlled, has an impressive potential

Normal eyeCorneal damage due to

Lost of corneal stem cells

The Eye

5

The pathophysiology

Damage of corneal

stem cells

The in vitro corneal reconstruction

1° step

The in vitro corneal reconstruction

2° step

SeveralControl steps oncultures

Integration in patients

Conjunctivalizationof ocular surface

(opacity)

Corneal restorationStem cell

“relocalization”

Surgery:Removal ofconjuctiva

from cornealsurface

Engraftment ofcultured limbuscontaining stem

cells

CulturedAutologous

Limbalepithelium

9

The clinical benefit

Before

After

Before After

(4 yr)now 11 y

(6 yr)now 13 y

(6,5 yr)now 13,5 y

(1,5 years)now10,5

Follow up at date ofpublication in brackets

CK12

Corneal marker restoration

Retrospective evaluationof the efficacy and safety

Date of production: 09/08/2010

Confirmed N° eyes Success Follow-up

Finaloutcome

139 72,8 % 10 years

Efficacy on long term

Academic setting (112 patients) GCP setting (139 patients)

EFFICACY ENDPOINT:Autologous Cultured Limbal Stem Cell

Transplant CLINICAL OUTCOMESAFETY POPULATION n=15

RESULTS

Success 60%

Failure 40%

Total 15

GMP/GCP setting (15 patients)

Clinical Safety

Retrospective evaluationConfirmed safety of procedure

Why long term follow up?

• To minimize risks of harm

• To maximize contribution to general knowledge

(results, meaning of researches, interpretability of data)

• To allow selection of the best treatments for the different types of patients

12

The steps to EU therapy

certification and spreading

2009:

Validation from regional authorities

- Inspectionfrom CNT

2009:

-Inspection from AIFA

2010:

--Inspection from AIFA

2011

-Acknowledgement

Of status of clinically consolidatedtherapy:

1° GMP-

treated patient

2014:-Question and answer from

Europeanmedicinal agency

2 Protocol Assistance with CAT

CAT definition of«Tissue Engineered Product,not combined» by CAT

Scientific Advice with PEI; Procedure of PA #3 with CAT; approval PIP by PEDCO

2015

- CONDITIONAL APPROVAL

OF THE FIRST STEM CELL PRODUCT

FOR COMMERCIALIZATION

IN EUROPE

2008:-

Orphan Medicinal Product

Designation by COMP

Definition of Advanced Therapy Medicinal Product by

ITF

2013-CTD:

Protocol Assistance with CAT

How to overtake HURDLES

• Public-private partnership

- share resources and money

- synergizes industrial and scientific know-how

- more efficient fund raising and projectplanning

- efficiently drives therapies to patients

• Public-private partnership requires well definedagreements and objectives

• The committment to these complex therapies requires well educated and responsible people

• Training of operators is patient-oriented

• Continuous training and re-training in the organization

• Matrix hierarchy to improve responsibility, interconnection between operators and best perception of the whole process

How to overtake HURDLES

• Treatments require different scientists, surgeons, regulators, and patients

Therefore

• Networking and planning together all activities

we connect patient’s association (i.e.: Debra Sud Tirol for gene therapy) with research activities

As well as a network of surgeons contributing to diagnosis and knowledge (i.e.: diagnosis wasquickened)

with common aims and credit

How to overtake HURDLES

What is requested from patient’s association

• Spread knowledge of pathologies, symptoms, quality of life, problems

(continuous updating on points to consider and long term results/risks)

• Life long cost of pathologies with no or poor therapeutic alternatives should be known

X X X

XXXXX

• Actively join the research projects

• Help scientist to have patient’s samples as well as normal control samples (often much more difficult to find)

• Harmonization of criteria/priority within the patient’s association

What is requested from patient’s association

National Geographic

Real, efficaceous and safe treatments

Transgene

GeneticallyDefective cells

GeneticallyCorrected autologous epithelium

Transplant

21

Centre for Regenerative Medicine

Full team

Alessandro Lambiase

Lorena Losi

Histology

AntonioPercesepeKaryology

Paolo Rama

Paolo e Andrea Chiesi

Fabio

Biscarini

Giuseppe Falini

Giuseppe

Falini

An

Francesco

Valle

AUGUSTO

Augusto Pocobelli

Monica Fantacci

Surgeons Other collaboratorsTHANK YOU FOR YOUR

ATTENTION!

Normal homeostasis:Segregation

of corneal regenerative propertiesin the human limbal area

CONTROLS on Several markersClonogenicity,microbiology

The in vitro corneal reconstruction

Stimulation of proliferation & differentiation

14-3-3 s

intermediate

1 mm biopsy

CULTURED CORNEALEPITHELIUM ON

SUBSTRATE

+

Rama et al., N.Engl.J.Med. 2010

Corneal regeneration by cultures of limbalstem cells

(up to 10 years follow-up in a mono-centric study)long term clinical results in 112 patients with chemical-burn (86.6% unilateral and 13.4% bilateral)

all patients had severe symptoms, loss of vision and no alternative therapy

KEY FIRST RESULTSRetrospective evaluation of the efficacy and safety of autologous cultivated

limbal stem cells transplantation for restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns

PROTOCOL NUMBER: HLSTM01Date of production: 09/08/2010

ANDRetrospective evaluation of the safety of autologous cultivated limbal stem

cell transplantation for restoration of corneal epithelium in patients withlimbal stem cell deficiency

PROTOCOL NUMBER: HLSTM02Date of production: 29/09/2010

GCP STUDY DOUBLE BLIND EVALUATIONconfirmed efficacy (72,8%) and safety of procedure

Limbal-corneal lesion

?

Vd PDA presentation

Talk scientFondaz hta strum accademia per portare terapia a pazienti

Per apporto know how ind + fund raisingChili di carte

OrganigrammaImp lavoro in rete con chiururghi e associaz paz ed debra sud tirol e aniridia

Spese viaggiom paz per diagnosi e progetti

- advice on how to accelerate drug development, based on your experience

- What should be changed in the classical regulatory and scientific environment ?

- What are the hurdles you are currently facing ? How are you planning to overcome them ?

- Graziella, I may ask you how you would compare cell (Holoclar) and gene therapyin this respect.

- Solutions to speed-up drug approval

- What patients can do, besides lobbying ?

Rama et al. New Engl.J.Med 2010Pellegrini, Ramaet al. Reg. Med. 2013

Long term clinical results in 154 patients( up to 14,5 years follow up, median of 8 years)

All patients had severe symptoms, loss of vision and poor or no alternative therapy

Corneal regeneration by cultures of limbal stem cells(up to 14,5 years follow-up in a multi-centric study)