HKU leads the Asia's first genetically

modified hematopoietic stem cell

transplantation for late juvenile

metachromatic leukodystrophy patient

(MLD)

Press Conference

May 20, 2015 1

Speakers

Dr Lian Qizhou

Assistant Professor

Department of Ophthalmology & Department of Medicine

Li Ka Shing Faculty of Medicine, HKU

Professor Zhuo Jiacai

Clinical Professor and Head of Division of Hematology

The Second People’s Hospital of Shenzhen

(The First Affiliated Hospital of Shenzhen University)

2

Courtesy from Dr Guili Nadinin

MLD is a devastating

lysosomal storage disease

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The Prevalence of MLD

Three Types of MLD observed

1.Infant Onset（Age 0-2, 50-60%）

-Early Infant (< Age 1 ) -Late Infant (Age 1-2)

2.Juvenile Onset (Age 2-16, 30-40%）

-Early Juvenile (Age 2-6 ) -Late Juvenile (Age 6-16)

3.Adult Onset（＞Age 16, ~5-10%)

Prevalence of MLD globally： 1.4–1.8 per 100,000 live births.

And there is 1,900 new MLD cases every year.

-Global: around 41,000 alive patients

-Mainland China: above 10,000 alive patients

-Hong Kong: estimated 40-50 alive patients

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No cure for MLD at Present

--Management of most MLD patients: Supportive care

--Developing new technology for MLD：

1.Hematopoietic stem cell transplantation (HSCT):

Bone marrow hematopoietic stem cell, Cord blood hematopoietic stem cell. Uncertain

outcome, confirmed ineffective in late infant onset

2. Enzyme replacement therapy (ERT)

Supply functional ARSA enzyme : high molecular weight protein, hard to pass the

blood–brain barrier (BBB),limited effects

3.Genetically modified hematopoietic stem cell

transplantation(HSCGT)： Lentiviral-mediated ARSA overexpression in autologous HSC following re-infusion

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The Principle of HSCGT to

Treat MLD

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Adapted from Dr Guili Nadinin

ARSA

Advantages of HSCGT for MLD

• Correction of Gene dysfunction in HSC

Expressing high level of functional ARSA; Lentiviral-mediated ARSA

gene insertion sites in host genome can be monitored

• Gene modified-HSC give rise to therapeutic cells

HSCs pass BBB in MLD patients, and give rise to microglia cells to

secrete ARSA enzyme , taken up by the recipient

neural cells

• Ensure to last efficacy in long term: Self-renewal of HSC

• No Immune Rejection: autologous HSC transplant

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HSCGT to Treat Late Infant MLD

at Early Pre-symptomatic Stage

Biffi, et al Science 2013

Rare Disease: Low Awareness

No Typical Symptom at early stage: Over 90% of patients

get wrong diagnosis and treatment

Progression : paralysis and blindness within 1-2 years in Late

infants; 6-8 years in Juvenile

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Most Identified MLD Patients Have

Developed into Middle-to-Late Stage

Late infant (< Age 2) Early Juvenile (Age 2-6) Late Juvenile (Age 6-16)

http://www.mldfoundation.org/mld-101-progression.html

A Typical Late Juvenile MLD with

Advanced-Stage

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Dysfunctions of cognitive

and mobility ability

MRI shown

demyelination in

brain

Low ARSA

activity, only

3-5% of healthy

level

ARSA gene

mutations

Procedures of HSCGT

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HSC mobilization

HSC collection HSC backup

Re-infuse gene modified HSC

Follow-up

Chemotherapy, Wipe out old HSC HSCGT

HSC Purification

Frozen & Quality Checks

Outsource for mass lentiviral

manufacturing (cGMP) Transfer gene into HSC

Gene design and construction

in modified lentiviral vectors

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Timeline of HSCGT

- 60d

1st time of HSC collection and

backup

2nd time of HSC collection and

Purification

- 35d - 30d - 10d

HSC genetically modification

Quality checks of genetically

modified HSC

-5d 0d

Chemo-conditioning ,wipe old

HSC with gene defects

30/60/180d

HSCGT

Efficacy and

Follow-up

Post-Transplantation(Follow-up)

Improvement

observed

Speech, Emotion,

Reaction

Mobility/Balance

Episodic Seizures,

Bowel movements

Blood: increased

ARSA activity (normal

ranges

76.6±29.9nmol/mg/hr） 13

MRI: no signs of further

deterioration

Improvement of mobility

Post-transplantation

14

2015,Post-Transplantation,

improved mobility/balance

capacity

2014 September, successful

chemo-conditioning &

transplantation

2012-14, 2 weeks per month in

hospital due to cognitive and motor

deterioration

Summary

1.MLD is a devastating lysosomal storage disease caused by a

deficiency of arylsulfatase A(ARSA). Without ARSA to breakdown

accumulated sufaltides, neural system is toxic and presents

progressive damage. Patients die within a few years and no cure in

current clinical management

2.Lentiviral-mediatated HSCGT offers a novel therapeutic

approach. This technology effectively increased ARSA activity and

arrest disease progress, and there is no increased risk of cancer

observed up to date

3.It is still hopeful to rescue MLD onsets with advanced-stage

before neural system is very severely damaged

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Acknowledgements

-HKU stem cells research team members

-Transplantation team members at the

Second People’s Hospital of Shenzhen

-Follow-up team members at The National

Taiwan University Hospital

-Taiwan Juridical Association of MLD Care

Patient’s Sharing

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Questions & Answers

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