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Program & Abstracts㤫ၽᡘⷔḌ౫⢐⛸Ⲁ಑ⱬྐྵ⯃Ⴠ⢙㔾⮯ᴫ㗡Ᏻᬫ㓡ᒛ

The 12th International Collaborative Forum of
Human Gene Therapy for Genetic Disease
Expanding clinical application of gene therapy for genetic diseasesరጙ⿫థጙ₂Ꮷಒᮎ⿫ఱథ
ర⢙⏠Ꮹಖ⢙㨃ᏧಒჀ⢙ἧ⏠ఱథర㙶ᑋఱథర⭙᭏ജ⭙⋳ఱವᐲಣჀ⢙࿂಑⏮ᰮⲀಎಇ౧ಉಒథ㓡ᒛ⒖၊ἃ ವ౷Ꮳ♮౲ಃ౸౧ద

President

2021年3月作成

Takanori Yamagata (Jichi Medical University))

DateJan. 20（Thu.）, 2022 ＊Hybrid Meeting

Venue

The Jikei University School of Medicine, Building 1 Hall

ファイザーは新しい時代を迎えました。
ザ

技術変革と最先端のサイエンスで、疾患の予防と治療に専念してまいります。

ファイザー株式会社 www.pﬁzer.co.jp

The 12th International Collaborative Forum of
Human Gene Therapy for Genetic Disease
第12回 国際協力遺伝病遺伝子治療フォーラム
Expanding clinical application of gene therapy for genetic diseases
飛躍する、遺伝病に対する遺伝子治療の臨床応用

Program & Abstracts

President
当番幹事

Takanori Yamagata (Department of Pediatrics, Jichi Medical University)
山形 崇倫（自治医科大学小児科学 主任教授）

Date

January 20（Thu.）, 2022 ＊Hybrid Meeting

Venue

The Jikei University School of Medicine, Building 1 Hall

Welcome Greetings

The 12th International Collaborative Forum of Human Gene
Therapy for Genetic Disease.
It is our honor to organize the 12th International Collaborative Forum of
Human Gene Therapy for Genetic Disease.
The development of gene therapy for a wide range of genetic diseases
has been on the rise worldwide. The main procedures available atpresent are in vivo gene therapy using an adeno-associated viral (AAV)
vector and ex vivo gene therapy using a lentiviral vector. Intravenous
Onasemnogene abeparvovec (zolgensma) treatment using an AAV9vector for spinal muscular atrophy was approved in Japan last year andhas since shown marked efficacy for patients treated early. In addition,
the advent of this treatment has helped familiarize many physicians with gene therapy as a whole.
Following the development of Onasemnogene abeparvovec, progress in AAV gene therapies forseveral diseases, including neurological diseases, such as AADC deficiency, congenital metabolic
diseases (mainly lysosomal diseases), and hemophilia has been achieved, and clinical trials
are underway. Ex vivo gene therapies using lentiviral vector have been developed for immune
deficiency as well as for neuronal and metabolic diseases, including adrenoleukodystrophy,
metachromatic leukodystrophy and Hurler disease.
We invited global front-runners in the clinical application of gene therapy to participate in thisforum. It is our great pleasure to have them here to inform us about the progress and benefitsof gene therapy. Gene therapy is a promising therapy, but some issues remain to be addressed.
Massive intravenous AAV gene therapy induced liver dysfunction and thrombocytopenia in somepatients, albeit transiently. Myelodysplastic syndrome was observed in some patients in lentiviralgene therapy. We have also invited prominent researchers to tell us more about gene therapy,
including its mechanism of action, expression control, and associated adverse events. We also
hope to learn more about the available support from the government for gene therapy.
We would enjoy hearing lectures directly from researchers and discussing their work in a faceto-face manner, but we understand that is difficult in the current global situation. Therefore, weplan to hold this forum in a hybrid system. Please join the forum either in person or attend via theweb. We hope this forum will be a good chance to learn about the worldwide progress of genetherapy, improving international/academic and pharmaceutical cooperation and stimulating further
research in this field in Japan.
We thank the participants as well as the individuals and companies who have supported thisforum.
Sincerely yours,

Takanori Yamagata
President of the 12th International Collaborative Forum of Human Gene Therapy for Genetic Disease
Professor,
Department of Pediatrics, Jichi Medical University
1

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Program（プログラム）
9:00~9:15

Opening Remarks（開会挨拶）
Takanori Yamagata (President of the 12th GT Forum)
山形

崇倫（第 12 回国際協力遺伝病遺伝子治療フォーラム 当番幹事）

Yoshikatsu Eto (Executive Chairperson of the Committee)
衞藤9:15~10:15

義勝（国際協力遺伝病遺伝子治療フォーラム 代表幹事）

Clinical experience of AAV-based gene therapy（AAV を用いた遺伝子治療の臨床）

Chairs: Torayuki Okuyama (National Center for Child Health and Development) /奥山

虎之（国立成育医療研究センター ライソゾーム病センター）

Kazuhiro Muramatsu (Jichi Medical University) /村松一洋（自治医科大学 小児科学）

1) O nasemnogene abeparvovec (Zolgensma®) for Spinal Muscular Atrophy:
Clinical and Real World Experience......................................................................... 6
Sandra P. Reyna (Novartis Gene Therapies, USA)2) Intracisternal AAV9-based Gene Therapy for Neuronopathic Lysosomal Storage
Diseases: Experience from a Clinical Trial Program................................................ 8
Marie-Laure Névoret (REGENXBIO, Inc., USA)
10:15~10:55

Special lecture（特別講演）
Chair: Keiya Ozawa (Jichi Medical University) /小澤敬也（自治医科大学 免疫遺伝子細胞治療学（タカラバイオ）講座）

Gene Therapy and Genome Editing for Human Genetic Diseases........................... 12James M. Willson (University of Pennsylvania, USA)
11:00~11:40

Special lecture（特別講演）
Chair: Yoshikatsu Eto (Institute of Neurological Disorders) /衛藤義勝（脳神経疾患研究所附属先端医療センター＆遺伝病治療研究所）

Advancing gene therapies for the brain..................................................................... 14
Beverly L. Davidson (University of Pennsylvania, USA)11:40~12:40

Gene therapy for Haemophilia（血友病の遺伝子治療）
Chairs: Toya Ohashi (The Jikei University School of Medicine) /大橋十也（東京慈恵会医科大学医学部看護学科）

Toshinao Kawai (National Center for Child Health and Development) /河合利尚（国立成育医療研究センター 小児内科系専門診療部 免疫科）

1) C linical Application of Gene Therapy for Hemophilia: Experience withfidanacogene elaparvovec and giroctocogene fitelparvovec............................... 18
Gregory Di Russo (Pfizer Inc., USA)2) Gene therapy of hemophilia A................................................................................ 20
Kevin Eggan (BioMarin Pharmaceutical Inc., USA)2

12:45~13:45

Luncheon Seminar（ランチョンセミナー）
Chair: Takanori Yamagata (Jichi Medical University) /山形

崇倫（自治医科大学 小児科学）

Takara Bio's efforts to address gene therapy vectors（遺伝子治療用ベクターに対するタカラバイオの取り組み）........................................................... 24

Tatsuji Enoki (Takara Bio Inc., Japan)
榎

13:55~14:25

竜嗣

Special lecture（特別講演）
Chair: Takashi Shimada (AMED/PMDA) /島田隆（AMED プログラムオフィサー、PMDA 専門委員）

Efforts on Gene and Cell Therapy Projects at AMED ............................................... 28
Michiko Takakura (AMED, Japan)
高倉 美智子（国立研究開発法人 日本医療研究開発機構）

14:25~15:25

Gene therapy for AADC deficiency（AADC 欠損症の遺伝子治療）
Chairs: Shinichi Muramatsu (Jichi Medical University) /村松慎一（自治医科大学 神経遺伝子治療部）

Hitoshi Osaka (Jichi Medical University) /小坂仁（自治医科大学 小児科学）

1) Gene therapy for aromatic L-amino acid decarboxylase deficiency in Japan improved
the motor and mental function of patients with various phenotypes........................ 32
Karin Kojima (Jichi Medical University, Japan)
小島

華林（自治医科大学 小児科学）

2) G ene therapy with rAAV2-hAADC for patients with aromatic L-amino aciddecarboxylase deficiency....................................................................................... 34
Wuh-Liang Hwu (National Taiwan University Hospital, Taiwan)
15:40~16:40

Ex vivo Gene therapy（Ex vivo 遺伝子治療）
Chairs: Hiroshi Kobayashi (The Jikei University School of Medicine) /小林博司（東京慈恵会医科大学 遺伝子治療研究部）

Toru Uchiyama (National Center for Child Health and Development) /内山徹（国立成育医療研究センター 成育遺伝研究部）

1) Hematopoietic stem cell gene therapy with a lentiviral gene delivery.................. 38
Naoya Uchida (The Institute of Medical Science, The University of Tokyo, Japan)
内田直也（東京大学医科学研究所 遺伝子・細胞治療センター）

2) Orchard Therapeutics and its Gene Therapy Programs........................................ 40
Christopher Dott (Orchard Therapeutics Ltd., UK)3

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

16:40~17:20

Special lecture（特別講演）
Chair: Masafumi Onodera (National Center for Child Health and Development) /小野寺

雅史（国立成育医療研究センター 遺伝子細胞治療推進センター）

Hematopoietic stem cell gene therapy for inborn errors of immunity andmetabolism.................................................................................................................. 44
Aiuti Alessandro (San Raffaele Telethon Institute for Gene Therapy, Italy)
17:20~17:40

Closing Remarks（閉会挨拶）
Ryuichi Morishita (President of the JSGCT, Osaka University)森下4

竜一（一 般社団法人日本遺伝子細胞治療学会 理事長、大阪大学 大学院医学系研究科臨床遺伝
子治療学）

Clinical experience of
AAV-based gene therapy-Abstracts & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Sandra P. Reyna
Address (Affiliation)

Novartis Gene Therapies

Field of ResearchChild Neurology, Neurology, Genetics

Education
Dr. Sandra P. Reyna received her M.D. degree from San Carlos
University Medical School in Guatemala and subsequently
pursued a career as a research physician in cardiovascularclinical genetics. She then trained in pediatrics at PrimaryChildren’s Hospital, Salt Lake City, Utah, and there
continued her medical training in Neurology and Genetics.
Professional ExperienceAs an Assistant Professor of Neurology at the University of Utah, she led the Neurology Clinical Trials Unit
as Director whilst keeping her appointment as Co-Director of the Pediatric Motor Disorders Research
Program; and as Project Director of NeuroNEXT and StrokeNet, for the National Institute of Health awards.
Since 2005, Dr Reyna’s academic career and research focus has been in neuromuscular disorders, withmuch of her time spent on Spinal Muscular Atrophy. Dr. Reyna led the SMA clinical trial network throughProject Cure SMA, funded by CureSMA, which led to the CARNI-VAL trials and publications.
After working at Massachusetts General Hospital from 2015 to 2016, she transitioned to her first industry
position at Biogen. There she participated in the physician development program, gaining experiencein Pharmacovigilance, Clinical Pharmacology and Clinical Development. She joined the SMA ClinicalResearch Development team and ultimately led all Nusinersen global trials with symptomatic and presymptomatic SMA affected children. She managed all medical aspects of the study, including medical
monitoring, investigator interactions, subject recruitment and retention, event adjudication, data
presentations, Global Steering Committee interactions and study data interpretation. She participatedin the filing for Nusinersen and supported the launch of SPINRAZA. In February 2019, she transitioned
to Bluebird Bio to work on gene therapy clinical trials for adrenoleukodystrophy. Throughout her time inindustry, Sandy has stayed involved in multiple SMA and other movement disorders, initiatives and interest
groups.
Currently she is Vice President of Medical Affairs, Global Therapeutic Area Head, where she is responsible
for the Global Medical Affairs plan for SMA aligned with Novartis Gene Therapies’ corporate strategy andtracking the execution of each tactic and in support of country launch teams.
Recent Related Publications (5 Papers)
1. D ay JW, Mendell JR, Reyna PS, et al.: Clinical Trial and Postmarketing Safety of Onasemnogene
Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119.
2. C hand DH, Zaidman C, Reyna SP, et al..: Thrombotic Microangiopathy Following Onasemnogene
Abeparvovec for Spinal Muscular Atrophy: A Case Series. J Pediatr. 2021 Apr 231:265-268
3. Elsheikh B, King W, Peng J, Reyna SP, et al.: Outcome measures in a cohort of ambulatory adults withspinal muscular atrophy. Muscle Nerve. 2020 Feb;61(2):187-191.
4. J ones CC, Cook SF, Reyna SP, et al..:Spinal Muscular Atrophy (SMA) Subtype Concordance in
Siblings:Findings From the Cure SMA Cohort.J Neuromuscul Dis. 2020;7(1):33-40.
5. De Vivo DC, Bertini E, Reyna SP,et al. ; NURTURE Study Group.: Nusinersen initiated in infants during
the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase
2 NURTURE study. Neuromuscul Disord. 2019 Nov;29(11):842-856.
6

Onasemnogene abeparvovec (Zolgensma®) for Spinal
Muscular Atrophy: Clinical and Real World Experience
Sandra P. Reyna
Novartis Gene Therapies

Spinal muscular atrophy (SMA) is a rare neurodegenerative disorder caused by the bi-allelicdeletion or mutation of the essential survival motor neuron 1 (SMN1) gene. Early intervention
is critical to halt irreversible loss of motor neurons and progressive muscle weakness for SMA
patients these individuals. Onasemnogene abeparvovec (ZOLGENSMA®) is a novel gene therapy
designed to target the genetic root cause of SMA and consists of an adeno-associated virus
serotype 9 vector containing a recombinant, self-complementary genome, a transgene encoding
the human SMN protein, under the control of a continuous cytomegalovirus enhancer / chicken-β-actin hybrid promoter. Over 1600 patients have been treated with intravenous (IV) onasemnogene
abeparvovec in 41 countries across clinical trials, managed access programs, and commercially.
Findings from the START, STR1VE-US, and STR1VE-EU trials, indicate that onasemnogene
abeparvovec significantly increases event-free survival in symptomatic patients with SMA type
1 compared with natural history. As of June 2020, all pre-symptomatic SMA patients with twoor three copies of SMN2 gene in the SPR1NT trial were alive and free of permanent ventilation.
No patient required feeding tube support, and the majority of patients achieved age-appropriate
milestones, such as sitting, standing, and walking.
The RESTORE registry provides real-world data for effectiveness of onasemnogene abeparvovec
patients beyond those studied in clinical trials, specifically patients who are 6 months of age
or older, and patients who weigh at least 8.5 kg. As of June 2021, the database comprised
information from 274 patients and 77 active sites.
The phase 3b SMART study aims to evaluate safety and efficacy of a one-time IV onasemnogene
abeparvovec dose in children with SMA weighing ≥8.5 kg and ≤21 kg. Enrollment is ongoing. The
intrathecal (IT) formulation is under investigation as a one-time, treatment option for older patientswith SMA. The phase 3 STEER study is estimated to start enrollment in December 2021 and aims
to evaluate the efficacy and safety of IT onasemnogene abeparvovec in patients with type 2 SMA
aged ≥2 to <18 years of age.
Across clinical studies and post-marketing surveillance, adverse events associated with IV
administration of onasemnogene abeparvovec are consistent and manageable. As of November
12, 2020, 101 of 102 (99%) patients experienced an adverse event, with 56.9% of patients
experiencing a serious adverse event (SAE), 10.8% considered related to treatment. The mostfrequently reported treatment-related SAEs were pyrexia and increased liver function tests,
which resolved with systemic corticosteroids. Transient platelet count decreases and cases ofthrombotic microangiopathy have also been identified from post-marketing experience.
Onasemnogene abeparvovec is an effective treatment for SMA with a safety profile that can be
anticipated, monitored, and managed. Durable efficacy and safety following a single IV dose
have been demonstrated for more than 5.6 years. For maximal clinical outcomes following earlyintervention, carrier and newborn screening for SMA are being implemented in several countries
around the world. Further collection of IV and IT treatment efficacy and safety in a broad SMA
patient population continues to be supported by ongoing clinical studies and emerging real-worlddata.
712th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Marie-Laure Névoret
Address (Affiliation)

REGENXBIO Inc.
9804 Medical Center Drive
Rockville, Maryland 20850
United States

Field of Research

AAV Gene Therapy

Education
Duke University

Loyola University Stritch School of Medicine
Loyola University Medical Center

B.A.
Chemistry with Biology
concentration and German Language
M.D.
General Surgery Residency

Professional Experience
Executive Director, Clinical Development Lead, Rare Diseases
Senior Clinical Development Lead, Rare Diseases
REGENXBIO, Inc.
Director, Global Clinical Development
Clinical Director
Global Medical/Clinical Trial Manager
Helixmith Co., Ltd (formerly ViroMed Co., Ltd)
Associate Director, Pharmacovigilance
PPD, LLC
Medical Director, North America
Impeto Medical, Inc.
Recent Related Publications (5 Papers)
1. Khalfallah K, Calvet JH, Brunswick P, Névoret M-L, Ayoub H, Cassir M. A Simple and Accurate Method
to Assess Autonomic Nervous System through Sudomotor Function. Advances in Biosensors: Reviews.
Volume 3, Chapter 6. Sep 2020.
2. Névoret M-L. Electrochemical skin conductance is sensitive and has clinical utility in patients withuntreated or poorly controlled diabetes. Letter to the editor. Biomedical Engineering Letters.
2019;9:507-509.
3. N
 évoret M-L., Vinik AI. What Can Sudorimetry Tell us about Somatic and Autonomic Function. J Cardiol& Cardiovasc Ther. 2018:11: JOCCT.MS.ID.555822.
4. Vinik AI, Névoret M-L. Diagnostic accuracy of neuropathy tests in obese population remains elusive. Clin
Neurophysiology. 2018;129:1502–1503.
5. Vinik AI, Casellini CM, Parson H, Colberg-Ochs SR, Nevoret ML. Cardiac Autonomic Neuropathy in
Diabetes: A Predictor of Cardiometabolic Events. Front. Neurosci. 2018;12:591.

8

Intracisternal AAV9-based Gene Therapy for Neuronopathic
Lysosomal Storage Diseases: Experience from a Clinical Trial
ProgramMarie-Laure Névoret
REGENXBIO, Rockville, MD, United States

MPS II is an x-linked lysosomal storage disease caused by deficiency of iduronate-2-sulfatase(I2S) leading to accumulation of glycosaminoglycans in tissues. Neuronopathic MPS II results inirreversible neurodevelopmental decline not addressed by intravenously administered enzyme
replacement therapy; gene therapy may offer a one-time treatment for genetic disorders withcentral nervous system (CNS) involvement such as MPS II. RGX-121, a recombinant adenoassociated virus serotype 9 capsid containing a human iduronate-2-sulfatase expression cassette(AAV9.CB7.hIDS), when administered to the CNS, may provide a permanent source of secreted
I2S, potentially correcting neurologic and systemic disease manifestations.
The route of administration used to optimize CNS biodistribution of the therapeutic transgene
while maintaining safety is critical. Early pre-clinical work demonstrated that intracisternal (IC)administration (suboccipital puncture) of AAV9 vectors expressing missing lysosomal enzymes
may have advantages over intracerebroventricular (ICV), intraparenchymal, or intrathecal (IT)lumbar puncture. Positron emission tomography biodistribution studies using [89ZR]-AAV9GFP in non-human primates showed that IC administration resulted in greater uptake in the brain(grey matter) compared to IT administration which shows greater uptake in the spinal cord. IC
administration has been adopted as the primary route for dosing RGX-121 in clinical trials, withimage-assisted ICV administration considered when IC may not be anatomically feasible. Prior
to vector administration, magnetic resonance imaging of the brain and C1-C2 intrathecal spaceis reviewed by a team of neuroradiologists and neurosurgeons to confirm patient suitability for
IC administration. Computed tomography-guided IC delivery is performed under anesthesia by atrained neuroradiologist or neurosurgeon.
In a phase 1/2, first-in-human, multicenter, open-label, dose escalation trial (NCT03566043),
participants with neuronopathic MPS II ages 4 months to 5 years receive one image-guided
RGX-121 injection to the CNS with follow-up for safety, tolerability, and efficacy for 104 weeks.
Assessments include cerebrospinal fluid, plasma and urine biomarkers; cognition, language, andmotor neurodevelopmental scales; and imaging. Nine participants have been enrolled in 3 dose
cohorts (1.3x1010, 6.5x1010, and 2.0x1011 genome copies/gram brain mass) as of April 25, 2021.
Following RGX-121 administration, there were consistent reductions of CSF heparan sulfate levels,a biomarker of neuronopathic MPS II disease. In addition, interim neurodevelopmental testing
demonstrated ongoing skill acquisition in multiple domains after RGX-121 administration. Plasma
I2S enzyme expression, total urine GAGs, and abdominal ultrasound imaging suggested emerging
evidence of systemic RGX-121 efficacy. Updated interim results from this clinical trial will bepresented.
RGX-121 gene therapy has the potential to provide sustained CNS clinical outcomes andadditional systemic effects in MPS II patients.

9

Memo

Special lectures-Abstracts & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

James M. Willson
Address (Affiliation)

Rose H. Weiss Professor and Director, Orphan Disease
CenterProfessor of Medicine and Pediatrics
Director, Gene Therapy Program
Perelman School of Medicine
University of Pennsylvania

Education
Albion College, Albion, MI					BAUniversity of Michigan, Ann Arbor, MI				
PhD
University of Michigan School of Medicine, Ann Arbor, MIMD

Chemistry
Biological Chemistry

Professional Experience
1988-1993	Assistant Professor to Associate Professor, Internal Medicine and Biological Chemistry,
University of Michigan
1988-1993	Assistant Investigator, Howard Hughes Medical Institute Medical School, University ofMichigan
1991-1993
Chief, Division of Molecular Medicine and Genetics, University of Michigan
1993-2000
Chief, Division of Medical Genetics, Department of Medicine, University of Pennsylvania
1993-2001	Professor and Chair, Department of Molecular and Cellular Engineering, University ofPennsylvania
1993-2002
Director, Institute for Human Gene Therapy, University of Pennsylvania
1994-2006
Professor of Pediatrics, University of Pennsylvania
1993-2005
Professor, The Wistar Institute1993-2009
John Herr Musser Professor of Research Medicine, University of Pennsylvania
2010
Visiting Professor, Dept. of Biochemistry and Molecular Biology, University of Florida
2006-2015	Professor of Pathology and Laboratory Medicine, Division of Transfusion Medicine,
University of Pennsylvania
2014-present Director, Orphan Disease Center, University of Pennsylvania
2006-present Director, Gene Therapy Program, University of Pennsylvania
2015-present	Professor of Medicine, Division of Translational Medicine and Human Genetics University ofPennsylvania
Recent Related Publications (5 Papers)
1. Martino RA, Fluck EC III, Murphy J, Wang Q, Hoff H, Pumroy RA, Lee CY, Sims JJ, Roy S, MoiseenkovaBell VY, Wilson JM. Context-Specific Function of the Engineered Peptide Domain of PHP. B. J Virol, Aug
4;JVI0116421, 2021.
2. Greig JA, Jennis M, Dandekar A, Chorazeczewski JK, Smith MK, Ashley SN, Yan H, Wilson JM. Muscledirected AAV gene therapy rescues the maple syrup urine disease phenotype in a mouse model. Mol
Genet Metab Aug 17;S1096-7192(21)00767-8, 2021. PMID: 34454844.
3. Tycko J, Adam VS, Crosariol M, Ohlstein J, Sanmiguel J, Tretiakova AP, Roy S, Worgall S, Wilson JM,
Limberis MP. Adeno-associated virus vector-mediated expression of anti-respiratory syncytial virus
antibody prevents infection in mouse airways. Hum Gene Ther, Aug 20, 2021. PMID: 34415793.
4. Wang Q, Nambiar K, Wilson JM. Isolating Natural Adeno-Associated Viruses from Primate Tissues witha High-Fidelity Polymerase. Hum Gene Ther, Aug 26, 2021. PMID: 34448594.
5. G reig JA, Smith MK, Nordin JML, Goode T, Chroscinski EA, Buza EL, Schmidt N, Kattenhorn LM,
Wadsworth S, Wilson JM. Determining the Minimally Effective Dose of a Clinical Candidate AAV Vector
in a Mouse Model of Hemophilia A. Hum Gene Ther, Oct 15, 2021. PMID: 34652966.

12

Gene Therapy and Genome Editing for Human Genetic
Diseases
James M. Willson
Perelman School of Medicine at the University of Pennsylvania

Gene Therapy and Gene Editing offer solutions to a wide array of rare monogenic diseases.
I will discuss our work using AAV vectors for neurologic diseases. I will also present studies inwhich we use gene editing for the treatment of neonatal onset liver metabolic diseases.

13

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Beverly L. Davidson
Address (Affiliation)

Education
Nebraska Wesleyan University B.S.		
University of Michigan		
Ph.D.						Postdoctoral

Pathology and Laboratory Medicine
Perelman School of Medicine
University of Pennsylvania

Biology
Biological Chemistry
Molecular Genetics

Professional Experience
1990-92
Research Investigator, Department of Internal Medicine, University of Michigan
1992-94
Assistant Research Scientist, Department of Internal Medicine, University of Michigan
1993-94
Director, Vector Core, Department of Internal Medicine, University of Michigan
1994
Assistant Professor, Department of Internal Medicine, University of Michigan
1994-98
Assistant Professor, Department of Internal Medicine, University of Iowa
1994-2013 Director, Gene Transfer Vector Core, University of Iowa
1998-2001 Associate Professor, Department of Internal Medicine, University of Iowa
2001-04
Co-Director, Iowa Biosciences Advantage Program for Gifted Minorities
2001-14
Professor, Departments of Internal Medicine, Neurology, Physiology & Biophysics
2005-14
Vice Chair for Research, Department of Internal Medicine, University of Iowa
2014- 	Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the
University of Pennsylvania
2014- 	Director, Raymond G. Perelman Center for Cellular and Molecular Therapy, The Children's
Hospital of Philadelphia
2014Arthur V. Meigs Chair in Pediatrics, The Children's Hospital of Philadelphia
2014Director, Research Vector Core, The Children's Hospital of Philadelphia
2016Chief Scientific Strategy Officer, The Children's Hospital of Philadelphia Research Institute
2016Committee on Appointments and Promotion, Perelman School of Medicine, UPENN
2016Dean's Advisory Council, Perelman School of Medicine, UPENN
2017Translational Neuroscience Center Scientific Advisory Board, UPENN
2017Neuroscience Advisory Committee, Mahoney Institute for Neuroscience (MINS), UPENN
Recent Related Publications
1. Monteys AM, Hundley AA, Ranum PT, Tecedor L, Muehlmatt A, Lim E, Lukashev D, Sivasankaran R,
Davidson BL. Regulated control of gene therapies by drug-induced splicing. Nature. 2021;596:291-295.
2. Tecedor L, Muehlmatt A, Davidson BL. Regulated control of gene therapies with a drug induced switch.
bioRxiv 2020.02.21.956664
3. Lang JF, Toulmin SA, Brida KL, Eisenlohr LC, Davidson BL. Standard screening methods underreport
AAV-mediated transduction and gene editing. Nat Commun. 2019;1:3415.
4. Victor MB, Richner M, Olsen HE, Lee SW, Monteys AM, Ma C, Huh CJ, Zhang B, Davidson BL, Yang XW,
Yoo AS. Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate
age-associated disease phenotypes. Nat Neurosci. 2018;21:341-352.
5. Yrigollen, CM, Davidson BL. CRISPR to the Rescue: Advances in Gene Editing for the FMRI Gene. Brain
Sci, 9(1):piiE17, 2019. PMC6357057

14

Advancing gene therapies for the brain
Beverly L. Davidson
Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania

15

Memo

Gene therapy for Haemophilia-Abstracts & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Gregory Di Russo
Address (Affiliation)

Pfizer Inc., USA

Field of Research

Clinical development of gene therapies
Biologics and small molecules in rare disease
Bleeding disorders
Transplantation
Cardiovascular diseases and pediatrics

Education
Johns Hopkins University		
Business of Medicine Certificate		
2004
Jefferson Medical College		MD						1991
Princeton University			AB: Romance Languages			1987
Professional Experience
Pfizer, Inc., Collegeville, PA
Vice President, Medicine Team Lead, Hemophilia, GPD Rare Disease2016-present
Asset Team Leader/Global Clinical Leader, Eliquis
2015-2016
CytoSorbents, Inc., Monmouth Junction, NJ. Senior Vice President, Clinical Development 2015
CSL Behring, King of Prussia, PA
Therapeutic Area Head - Acquired Bleeding and Head of Specialized Sciences
2014
Therapeutic Area Head - Acquired Bleeding
2013-2014
Senior Global Clinical Program Director - Acquired Bleeding/Critical Care
2011-2013
Program Director – Acquired Bleeding/Critical Care
2011
Bristol-Myers Squibb, Princeton, NJ - Global Clinical Development
Director – CV/Metabolics
2010-2011
Director – Immunology
2007-2010Children’s National Medical Center/George Washington University, Washington, DC
Vice Chairman of Cardiovascular Surgery
2001-2005
Director of Cardiac Transplantation, Assistant Professor of Surgery
Primary Children’s Medical Center/University of Utah School of Medicine, Salt Lake City, Utah
Assistant Professor of Surgery
1999-2001
Recent Related Publications
1. Byon W, Cirincione B, Di Russo G, et al. The renal elimination of apixaban: the totality of data relating
to the renal clearance of apixaban in patients with impaired renal function: response to Hellfritzsch et al.
Pharmacoepidemiol Drug Saf. 2017;26:603-605.
2. Larsen CP, Grinyó J, Di Russo GB, et al. Belatacept-Based Regimens Versus a Cyclosporine A-Based
Regimen in Kidney Transplant Recipients: 2-Year Results From the BENEFIT and BENEFIT-EXT Studies.
Transplantation 2010;90:1528-35.
3. Durrbach A, Pestana JM, Di Russo GB, et al. A Phase III Study of Belatacept Versus Cyclosporinein Kidney Transplants From Extended Criteria Donors (BENEFIT-EXT Study). Am J Transplantation
2010;10:547-57.
4. Vincenti F, Charpentier B, Di Russo GB, et al. A phase III study of belatacept-based immunosuppression
regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant.
2010;10:535-46.
5. Benjamin LC, Nahar J, Sable C, Midgley FM, Di Russo GB. Separation of thoracopagus-cardiopagus
twins joined by a myocardial bridge. J Thorac Cardiovasc Surg. 2005;130:1212-3.

18

Clinical Application of Gene Therapy for Hemophilia:
Experience with fidanacogene elaparvovec and giroctocogene
fitelparvovec
Gregory Di Russo
Pfizer Inc., USA

Hemophilia A/B is a rare bleeding disorder caused by pathogenic variants in the F8/F9 gene. Adenoassociated virus (AAV)–mediated gene transfer enables the delivery of a modified functional F8/F9 coding
sequence to hepatocytes that subsequently synthesize FVIII/FIX at levels that may prevent bleeding events.
We present updated results with nearly 2-year follow-up from an ongoing gene therapy study in patientswith hemophilia A (NCT03061201), and more than 5-year follow-up in a cohort of patients with hemophilia
B (NCT02484092). Hemophilia A Eleven patients with hemophilia A (FVIII activity <1%) were treated withgiroctocogene fitelparvovec in 4 dose cohorts (9e11, 2e12, 1e13, and 3e13 vg/kg) in the phase 1/2 study. Asof the cutoff date, patients had been followed for 95 to 195 weeks overall. Treatment-related serious AEs
were reported in 1 patient who experienced hypotension and fever. ALT elevations requiring >7 days ofcorticosteroid treatment were observed in 4 of the 5 patients in the 3e13-vg/kg cohort. For the 4 patientsin the 3e13-vg/kg cohort, patients had mean FVIII activity maintained in the mild to normal range throughweek 104. The annualized bleeding rate was 0 for the first year postinfusion and 0.9 throughout the total
duration of follow-up. 2 patients experienced a total of 3 bleeding events necessitating treatment withexogenous FVIII. No patients in have resumed prophylaxis. Hemophilia B Fifteen patients with hemophilia
BFifteen patients with hemophilia B (FIX(FIX activity ≤activity ≤2%)2%) were treated with fidanacogene
were treated with fidanacogene elaparvovec at a dose of 5e11 vg/kg. All 15 patients completed the phase1/2a studyelaparvovec at a dose of 5e11 vg/kg. All 15 patients completed the phase 1/2a study ((52 52
weeksweeks)), and 14 patients were subsequently enrolled in the , and 14 patients were subsequently
enrolled in the longlong--term followterm follow--up (LTFU)up (LTFU) studystudy ((5 years5 years)). . As of
the cutoff date, 13 patients were enrolled in the LTFU study, with follow, 13 patients were enrolled in the
LTFU study, with follow--up ranging up ranging from >2.5 years to >5 years following vector administration.
3 patients were treated with from >2.5 years to >5 years following vector administration. 3 patients weretreated with corticosteroids within the first 6 months of the phase 1/2a study. There were no serious
corticosteroids within the first 6 months of the phase 1/2a study. There were no serious adverseadverse
events (SAEs) in the phase 1/2a study, and 3 patients reported SAEs in the LTFU events (SAEs) in the phase1/2a study, and 3 patients reported SAEs in the LTFU study, none of which were considered treatment
related. study, none of which were considered treatment related. Mean FIX activity levels by year remain in
the mild hemophilia severity rangeMean FIX activity levels by year remain in the mild hemophilia severity
range,, associated with associated with mean annualized bleedinmean annualized bleeding rates ranging
from 0g rates ranging from 0––0.9 over the course of follow0.9 over the course of follow--up, and noup, and no patients have resumed FIX prophylaxis. Four patients have undergone 6 surgical procedures
patients have resumed FIX prophylaxis. Four patients have undergone 6 surgical procedures during the
LTFU study. There were no bleeding complications with these procedures, and the during the LTFU study.
There were no bleeding complications with these procedures, and the 2 emergent 2 emergent procedures(appendectomy and lumbar discectomy) were performed without the procedures (appendectomy andlumbar discectomy) were performed without the need of additional FIX. need of additional FIX.
Overall, both a single infusion of giroctocogene fitelparvovec in patients with hemophilia A andfidanacogene elaparvovec in patients with hemophilia B were generally well tolerated with associatedincreases in FVIII/FIX levels in the mild to normal range, without sustained AEs, and with minimal bleeding.
Phase 3 studies of giroctocogene fitelparvovec in patients with hemophilia A (NCT04370054) andfidanacogene elaparvovec in patients with hemophilia B (NCT03861273) are ongoing.

19

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Kevin Eggan
Address (Affiliation)

BioMarin Pharmaceutical Inc.

Field of Research

Genetic Disease

Education
University of Illinois
B.S.
MIT			Ph.D.

Microbiology
Biology

Professional Experience
Kevin Eggan, Ph.D., joined BioMarin as Group Vice President, Head of Research and Early Developmentin 2020. He is responsible for the execution of BioMarin’s discovery research programs, playing a criticalrole in shaping the vision of the company’s future research pipeline. He heads BioMarin’s Researchorganization, providing scientific leadership throughout the drug discovery process. Dr. Eggan is charged
with further building BioMarin’s leadership position in genetic medicines in support of people affected byrare genetic diseases and contributing to the long-term growth of BioMarin through the oversight of an
exceptional pipeline of first- or best-in-class therapies. Dr. Eggan has served as a tenured Professor in the
Department of Stem Cell and Regenerative Biology at Harvard University, Director of Stem Cell Biology for
the Stanley Center for Psychiatric Research at the Broad Institute, and as an Institute Member of the Broad
Institute of MIT and Harvard. In addition, Dr. Eggan has published approximately 130 scientific articles
and holds 13 patents. He has served on the Scientific Advisory Boards of Ipierian, Roche, and Angelini
Pharma among others. He has co-founded three biotechs, Q-State Bioscience, Quralis, and Enclear
Therapies which have raised more than $85 million of investment. He has also collaborated with Ipierian on
establishing human neuronal models that were later used to discover and characterize an anti-Tau antibody
that is currently part of Biogen’s portfolio for a potential treatment of Alzheimer’s disease.
Dr. Eggan resolved early in his academic career to raising support for the stem cell research community atlarge. While he has been involved in a variety of efforts outside of Harvard, Dr. Eggan worked from 2005
until 2015 with The New York Stem Cell Foundation (NYSCF) and their CEO Susan Solomon to raise morethan $200 million for stem cell research. Amongst the most impactful of these efforts has been the ability
to raise more than $100 million for young investigator programs in stem cell biology and neurosciencethat have supported more than 70 five-year awards to junior faculty and fellowships for 75 postdoctoral
trainees.
Dr. Eggan received his B.S. in microbiology at the University of Illinois and his Ph.D. in biology from M.I.T.
where he focused on cloning, stem cells, and reprogramming after nuclear transfer under the guidance of
Rudolph Jaenisch, Ph.D. a scientific pioneer in genetics. Dr. Eggan remained in the lab of Dr. Jaenisch fora one-year post-doctoral position at the Whitehead Institute for Biomedical Research where he conducteda study with Nobel laureate Richard Axel, M.D. Dr. Eggan has received international recognition for his
work including receiving the MacArthur Foundation’s “Genius Grant.” He has also been named one of 50
Howard Hughes Medical Institute Early Career Scientists, one of the 50 Most Influential People in Scienceby Scientific American two years in a row, Innovator of the Year by Technology Review Magazine, a Top
Innovator under 35 by Technology Review Magazine, and a “Brilliant 10” by Popular Science Magazine.
Recent Related Publications
1. Burberry A, Wells M, Eggan K, et al. C9orf72 suppresses systemic and neural inflammation induced by
gut bacteria. Nature. 2020;582:89-94.
2. Hazelbaker DZ, Beccard A, Eggan K, et al.. A multiplexed gRNA piggyBac transposon system facilitatesefficientinduction of CRISPRi and CRISPRa in human pluripotent stem cells. Sci Rep. 2020;10:635.
3. Oh HS, Neuhausser WM, Eggan KC, et al. Herpesviral lytic gene functions render the viral genome
susceptible to novelediting by CRISPR/Cas9. Elife. 2019;8:e51662.
4. Farhan SMK, Howrigan DP, Eggan K, et al. Exome sequencing in amyotrophic lateral sclerosis implicatesa novel gene, DNAJC7, encoding a heat-shock protein. Nat Neurosci. 2019;22:1966-1974.
20

Gene therapy of hemophilia A
Kevin Eggan
BioMarin Pharmaceutical Inc.

BACKGROUND
A single infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) resulted in clinically significant
Factor VIII (FVIII) activity levels and reduced annualized bleeding and FVIII utilization over 5
years of follow-up. Previous studies showed durable expression is associated with presence of
circularized episomal DNA in target tissues. AAV5-hFVIII-SQ, an oversized vector, drives FVIII
expression using a liver specific promoter, but vector DNA presence in hepatocytes has not been
confirmed through liver biopsy.
AIMS
To evaluate histopathology and vector genome forms and distribution in human liver biopsies
following AAV5-hFVIII-SQ administration.
METHODS
Liver biopsies were obtained from five participants receiving 6x1012, 4x1013 or 6x1013 vg/kg
doses of AAV5-hFVIII-SQ. Biopsy samples collected 2.6-4.1 years following dosing underwent
histopathological examination, and in situ hybridization to detect vector genomes.
RESULTSHistopathological examination revealed normal liver architecture, no evidence of dysplasia,
architectural distortion, fibrosis, or chronic inflammation, and no endoplasmic reticulum stress
was detected in hepatocytes expressing hFVIII-SQ protein. Mild steatosis was detected in fourout of five participants. Hepatocytes stained positive for vector genome dose-dependently
and molecular analysis demonstrated the presence of full-length, ITR-fused, circular episomal
genomes, which are associated with long-term expression.

21

Memo

Luncheon Seminar-Abstract & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Tatsuji Enoki

Education
Osaka Prefecture University
Osaka Prefecture University
Kagoshima University		

Address (Affiliation)

Takara Bio Inc., Japan

Field of Research

Gene therapy, Immunology and Stem cell research

B.A.
M.A.
Ph,D.

1993
1995
2012

Agricultural Chemistry
Agricultural Chemistry
Agriculture

Professional Experience
1995 – 2002
Takara Shuzo Co. Ltd.
2002 – 2004
Takara Bio Inc.*
2004 – 2016
Takara Bio Inc., Senior Scientist,(Oct. 2010 – Jul. 2011 Dr. Nakai Lab., University of Pittsburgh )2016 – 2017
Takara Bio Inc., Deputy General Manager,
2017 – present Takara Bio Inc., General Manager*(successor-in-interest of Takara Shuzo Co., Ltd. Biomedical Group)
Recent Related Publications
1. O kamoto S, Amaishi Y, Maki I, Enoki T, Mineno J. Highly efficient genome editing for single-basesubstitutions using optimized ssODNs with Cas9-RNPs. Sci Rep., 9(1):4811. doi: 10.1038/s41598-01941121-4, 2019.
2. Ishikawa T, Okayama T, Sakamoto N, Ideno M, Oka K, Enoki T, Mineno J, Yoshida N, Katada K, Kamada
K, Uchiyama K, Handa O, Takagi T, Konishi H, Kokura S, Uno K, Naito Y, Itoh Y. Phase I clinical trialof adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients withgastric or colorectal cancer. Int J Cancer, doi: 10.1002/ijc.31285, 2018.
3. Hosoi H, Ikeda H, Imai N, Amaike C, Wang L, Orito Y, Yamane M, Ueno H, Ideno M, Nukaya I, Enoki T,
Mineno J, Takesako K, Hirano S, Shiku H. Stimulation through very late antigen-4 and -5 improves themultifunctionality and memory formation of CD8+ T cells. Eur J Immunol., 44(6): 1747-1758, 2014.
4. Ishikawa T, Kokura S, Enoki T, Sakamoto N, Okayama T, Ideno M, Mineno J, Uno K, Yoshida N, Kamada
K, Katada K, Uchiyama K, Handa O, Takagi T, Konishi H, Yagi N, Naito Y, Itoh Y, Yoshikawa T. Phase I
clinical trial of fibronectin CH296-stimulated T cell therapy in patients with advanced cancer. PLoS One,9(1): e83786, 2014.
5. Adachi K, Enoki T, Kawano Y, Veraz M, Nakai H. Drawing a high-resolution functional map of adenoassociated virus capsid by massively parallel sequencing. Nat Commun., 5: 3075, doi:10.1038/
ncomms4075, 2014.

24

Takara Bio's efforts to address gene therapy vectors
Tatsuji Enoki
Takara Bio Inc., Japan

遺伝子治療用製剤の開発においては、in vivo、ex vivo のいずれにおいてもウイルスベクターが広く利用されている。ウイルスベクターの開発過程では、ベースとなるベクターの選定及び設計、ベクターの調製、タイターの測定等、多くの研究用ツールが利用される。
当社においては、レトロネクチン ® による造血幹細胞や T 細胞への遺伝子導入法の開発を契機に、遺伝子治療用ウイルスベクターに対する検討を継続して行っており、最近では、アデノ随伴ウイルス（AAV）
ベクターに関してセロタイプを問わず培養上清と細胞内からまとめて精製できる手法や、臨床応用を想定して HIV-1 由来配列を極力削減したレンチウイルス（LV）ベクターを開発し、研究用ツールとして提供している。また、ウイルスベクターの GMP 受託製造サービスにおいて、AAV ベクター等の臨床応用のためには大量のベクター量が必要となることがあるため、その GMP 製造に対応するための設備の拡充を進めている。
今回、これら LV ベクター及び AAV ベクターを中心に、遺伝子治療用ウイルスベクターに対する当社の取り組みについて紹介する。

25

Memo

Special lecture-Abstract & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Michiko Takakura
Address (Affiliation)

Deputy Manager,
Division of Gene Therapy
Department of Regenerative Medicine and Cell andGene Therapies
Japan Agency for Medical Research and Development(AMED)
21F Yomiuri Shimbun Bldg. 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004 Japan

Field of Research

Biochemistr y, Molecular biology, Cell and Gene
Therapies

Education
Graduate School of Environmental Health, Azabu University -Doctor of Science and Culture (Ph.D.)
Professional Experience
2020-present	AMED-Division of Gene Therapy Department of Regenerative Medicine and Cell and Gene
Therapies
2018-2020	AMED-Division of Drug Research Depar tment of Innovative Drug Discover y andDevelopment, Responsible for Project Management of Research and development of coretechnologies for gene and cell therapy
2017-2018	AMED-Division of Rare/Intractable Disease Research Department of Research Promotion,
Member of the AMED-Task Force of the IRUD (Initiative on Rare and Undiagnosed Diseases)
and IRDiRC (International rare disease research consortium)
2015-2017	Division of Biological Chemistry and Biologicals, National Institute of Health Sciences,
Project Member of Evaluating and predicting the activation of human immune cells by novel
Fc-engineered mAbs
Recent Related Publications (5 Papers)
1. Michiko Takakura, et.al. Biochem Biophys Res Commun. 2017 Mar 25;485(1):189-194
2. Michiko Takakura, et.al. ISRN Oncology. Vol. 19, 1-10, 2012,
3. Michiko Takakura, et.al. Cancer Biomarkers. Vol.10 (3-4), 175-183, 2011/2012.

28

Efforts on Gene and Cell Therapy Projects at AMED
Michiko Takakura
AMED, Japan

Since its establishment as a national research and development (R&D) agency in 2015, the Japan
Agency for Medical Research and Development (AMED) has worked to promote seamless R&D in
medicine and related areas, extending from basic research to practical application, and to apply
the outcomes of such research in practice.
In 2020, AMED’s Second Medium- to Long-Term Plan was launched. During the second plan
period, we will further advance and consolidate the results we achieved during the five years of
the first plan, thoroughly verifying the issues that remain, as we seek to forge a smoother path
toward a strong structure and operations. The key concern among issues that have been raised
relates to the integrated projects under the first plan, comprising five cross-sectional projects andfour disease area-specific projects. It allocates funding to six projects according to therapeutic
approaches and modalities, one of which is the “Project for Regenerative / Cellular Medicine andGene Therapies”.
The project supports basic, non-clinical and clinical research on regenerative and cellular
medicine to promote studies of fundamental technologies and to develop regenerative medical
products. In addition, it covers research on gene therapies to put in practice or to contribute theadvancement of this area of therapeutics. Research includes therapies by in vivo, ex vivo delivery,
oncolytic virus, and gene editing, to develop novel treatment for incurable diseases, especiallycancers and rare disorders.
Today, I will introduce our efforts and activities for R&D on gene therapies, financial supports
for non-clinical and clinical research on gene therapies for cancers and rare disorders, and the
project to support practical application of gene therapies. For those of cancers, we are supporting
14 programs this fiscal year. Nine are for CAR T-cell therapies and three are therapies that utilize
oncolytic virus. For rare and intractable diseases, we support ten programs. Of which eight are forin vivo gene therapies, and one program each for ex vivo gene therapies and gene editing.
The project designed to contribute to the advancement of gene therapy will integrate advanced
key technologies scattered in Japan into core centers to develop new large-scale vector
production methods, create a network of research centers with these large-scale production
technologies, and establish a basis for research on novel gene/cell therapy with the overarchinggoal of its eventual clinical application. Another goal is the acceleration of R&D on advanced
gene/cell therapy by creating new technologies for high-quality production and improved safety
required to reach clinical use. Taken together, we work with the aim to develop and implement
gene therapies for incurable diseases, to give patients a way to novel treatment in the near future.

29

Memo

Gene therapy for AADC deficiency-Abstracts & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Karin Kojima
Address (Affiliation)

Department of Pediatrics, Jichi Medical University

Field of ResearchChild neurology, gene therapy

Education
2001 Graduated from Faculty of Medicine, Jichi Medical University, Japan
2014 Graduated from Graduate School, Jichi Medical University, Japan
Professional Experience
2001 Junior resident of internal medicine, Aomori Prefectural Central Hospital, Japan
2003 Medical director of internal medicine. National Health Insurance Hospital in Aomori
2007 Senior resident of pediatrics, Jichi Children’s Medical Center Tochigi, Japan
2008 Medical director of Pediatric, Public health hospital in Nagasaki, Japan
2014 Research associate, Department of Pediatrics, Jichi Medical University
2017 Assistant Professor, Department of Pediatrics, Jichi Medical University
2019	Postdoctoral associate, Dr. Parchem lab, Center for Gene Therapy, Baylor College of Medicine, TX,
US
2021 Manager in Pediatrics, Tochigi rehabilitation center hospital, Japan
Recent Related Publications (5 Papers)
1. Kojima K, Nakajima T, Taga N, Miyauchi A, Kato M, Matsumoto A, et al. Gene therapy improves motorand mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019;142(2):322-33.
2. Keuls R, Kojima K, Lozzi B, Steele J, Chen Q, Gross S, et al. Mir-302 Regulates Glycolysis to Control
Cell-Cycle during Neural Tube Closure. Int J Mol Sci. 2020;21(20):7534. soi: 10.3390/ijms21207534.
3. Onuki Y, Ono S, Nakajima T, Kojima K, Taga N, et al. Dopaminergic restoration of prefrontal corticoputaminal network in gene therapy for aromatic l-amino acid decarboxylase deficiency. Brain Commun.
2021:3(3):fcab078.doi: 10.1093/braincomms/fcab078.
4. Kuwajima M, Kojima K, Osaka H, Hamada Y, Jimbo E, et al. Valine metabolites analysis in ECHS1
deficiency. Mol Genet Metab Rep. 2021;(29):100809. doi: 10.1016/j.ymgmr.2021.100809.
5. K ojima K, Anzai R, Ohba C, Goto T, Miyauchi A, Thony B, et al. A female case of aromatic l-amino aciddecarboxylase deficiency responsive to MAO-B inhibition. Brain Dev. 2016;38(10):959-63

32

Gene therapy for aromatic L-amino acid decarboxylase deficiency
in Japan improved the motor and mental function of patients withvarious phenotypes
Karin Kojima
Jichi Medical University, Japan

Aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM #608643) is an autosomal
recessive neurotransmitter disorder caused by defects in the DDC gene, which encodes AADC.
AADC catalyzes the formation of neurotransmitters from L-DOPA and 5-hydroxytryptophan to
dopamine and serotonin, respectively. The main phonotype of AADC deficiency is movement
disorder, including loss of voluntary movements, hypotonia, intermittent oculogyric crisis (OGC)
and trunk dystonia. Patients also present with autonomic dysfunction, intellectual disability andemotional instability. Patients with AADC deficiency are classified as severe type (80%: bedridden
and fully dependent), mild (5%: ambulatory without assistance, intellectual disability) or moderate(15%: between severe and mild). Since 2015, we have been performing gene therapy for AADC
deficiency as a clinical study using the AAV2 vector carrying the DDC gene (AAV2-AADC), which
expresses AADC. Eight patients with AADC deficiency (seven severe type and one moderate type)were subjected to gene therapy via the injection of AAV2-AADC into both sides of the putamen
during stereotactic brain surgery.
We herein report the long-term course after gene therapy. Over a maximum of six and a halfyears after gene therapy, improvement of symptoms has continued in all cases, albeit to varying
degrees. Before treatment, the seven severe-type patients had no head control even with fullassistance and frequent dystonia attacks. However, all of these severe patients are now able tocontrol their heads, and six are able to use walkers. Dystonia attacks disappeared in all patients.
And their autonomic dysfunction also improved. The moderate-type patient was able to walk withassistance before gene therapy but could walk independently after gene therapy and is now able
to go to school on her own. She also showed intellectual development and has now reached anormal level.
Positron emission tomography (PET) using FMT, an AADC tracer, showed that the FMT
accumulation in the putamen after five years was at the same level as at six months after
treatment, and the effect of gene therapy was sustained for a long period of time. The resting
functional MRI activity was compared before and after surgery, and the functional connectivity ofthe basal ganglia centered on the putamen was improved after treatment.
In a series of eye-tracking assessments, we conducted three types of tests: gap-overlap, word
comprehension, and perspective-taking tasks. We explored the developmental trajectories ofthese tasks in patients with AADC. Although there was a difference in efficacy depending on theseverity of the gene mutation site and the age at the time of treatment, gene therapy improved
clinical symptoms in all cases, and the effect of gene therapy was maintained even after six years.
The recovery of dopamine in the putamen by this treatment is believed to have promoted thefunctional recovery of the basal ganglia network.
We are currently preparing for a clinical trial.
33

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Wuh-Liang Hwu
Address (Affiliation)

Department of Pediatrics and Medical Genetics
National Taiwan University Hospital (NTUH)
8 Chung-Shan South Road, Taipei 10041, Taiwan

Field of Research

Pediatrics, Genetics, Gene therapy

Education
College of Medicine, National Taiwan University
Institute of Molecular Medicine, National Taiwan University

M.D.
Ph.D.

Professional Experience
Director, Department of Medical Genetics, National Taiwan University Hospital 2006-2012
Deputy Director, Department of Pediatrics, National Taiwan University Hospital 2018-2021
Professor, Department of Pediatrics, National Taiwan University Hospital
2010-now
Recent Related Publications
1. T ai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, Hwu WL. Long-Term
E f ficacy and Safet y of Eladocagene E xupar vovec in Patients with A ADC Deficiency. Mol
Ther.2021:S1525-0016(21)00576-1
2. Hwu PW, Kiening K, Anselm I, Compton DR, Nakajima T, Opladen T, Pearl PL, Roubertie A, Roujeau T,
Muramatsu SI. Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease. EMBO
Mol Med. 2021;13:e14712.
3. Tseng CH, Chien YH, Lee NC, Hsu YC, Peng SF, Tseng WI, Hwu WL. Gene therapy improves brain whitematter in aromatic l-amino acid decarboxylase deficiency. Ann Neurol. 2019 May;85:644-652.
4. Chien YH, Lee NC, Tseng SH, Tai CH, Muramatsu S, Byrne BJ, Hwu WL. Efficacy and safety of AAV2
gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2
trial. Lancet Child Adolesc Health. 2017;1:265–73
5. Lee NC, Lee YM, Chen PW, Byrne BJ, Hwu WL. Mutation-adapted U1 snRNA corrects asplicing error ofthe dopa decarboxylase gene. Hum Mol Genet. 2016;25:5142-5147

34

Gene therapy with rAAV2-hAADC for patients with aromaticL-amino acid decarboxylase deficiency
Wuh-Liang Hwu
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorderresulting in congenital deficiency of dopamine, serotonin, and downstream monoamine
neurotransmitters. Patients with severe AADC deficiency present hypokinesia and dystonic since
early infancy, followed by a characteristic movement disorder, oculogyric crisis (OGC). In a natural
history study in Taiwan, patients usually stopped growing after one year of age, and most ofpatient didn’t develop any meaningful motor milestone, including head control.
Three clinical trials have been conducted in Taiwan, employing a recombinant adeno-associatedvirus serotype 2 containing the human cDNA encoding the AADC enzyme (rAAV2-hAADC). Viral
vector was administered bilaterally in the putamen with a total of 1.8 × 1011 vg or 2.4 × 1011 vg.
Patients were assessed using the Peabody Developmental Motor Scales, 2nd Edition (PDMS2) and 18F-DOPA-PET. We recently published the treatment outcomes of 26 patients. Increase in
PDMS-2 score and PET signal were seen in all patients. Improvements in non-motor symptoms,
including emotion instability, OGC, excessive sweating, and temperature instability, were also
seen. Younger age at the time of treatment was a significant prognostic factor.
The most commonly reported TEAEs across all three studies were pyrexia and dyskinesia. Postgene transduction dyskinesia was transient and may be related to receptor hypersensitivity. In
conclusion, this gene therapy is safe and highly effective. It is currently under commercialization
by PTC therapeutics as a brand name of Eladocagene exuparvovec.

35

Memo

Ex vivo Gene therapy-Abstracts & Curriculum Vitae-

37

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Naoya Uchida

Education
Nippon Medical School		
Nippon Medical School		

Address (Affiliation)

Division of Molecular and Medical Genetics,
Center for Gene and Cell Therapy,
The Institute of Medical Science, The University ofTokyo

Field of Research

Hematopoietic stem cell transplantation, Gene therapy,
Genome editing, Lentiviral vector

Ph.D.
M.D.

Professional Experience
2020-present Associate Professor in Division of Molecular and Medical Genetics, Center for Gene andCell Therapy, The Institute of Medical Science, The University of Tokyo, Japan
2009-present Staff Scientist in Cellular and Molecular Therapeutics Branch
NHLBI, NIH, Bethesda, MD, USA
Recent Related Publications (5 Papers)
1. Uchida N*, Li L, Nassehi T, Drysdale CM, Yapundich M, Gamer J, Haro-Mora JJ, Demirci S, Leonard
A, Bonifacino AC, Krouse AE, Linde NS, Allen C, Peshwa MV, De Ravin SS, Donahue RE, Malech HL,
Tisdale JF. Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease
locus in xenograft mouse and non-human primate models. Cell Rep Med. 2021 Apr 20;2(4):100247.
2. U chida N*, Ferrara F, Drysdale CM, Yapundich M, Gamer J, Nassehi T, DiNicola J, Shibata Y, Wielgosz M,
Kim YS, Bauler M, Throm RE, Haro-Mora JJ, Demirci S, Bonifacino AC, Krouse AE, Linde NS, Donahue
RE, Ryu BY, Tisdale JF. Sustained fetal hemoglobin induction in vivo is achieved by BCL11A interference
and coexpressed truncated erythropoietin receptor. Sci Transl Med. 2021 Apr 28;13(591):eabb0411.
3. Drysdale CM, Nassehi T, Gamer J, Yapundich M, Tisdale JF*, Uchida N*. Hematopoietic-Stem-CellTargeted Gene-Addition and Gene-Editing Strategies for β-hemoglobinopathies. Cell Stem Cell. 2021
Feb 4;28(2):191-208.
4. Hsieh MM, Bonner M, Pierciey FJ, Uchida N, Rottman J, Demopoulos L, Schmidt M, Kanter J, Walters
MC, Thompson A, Asmal M, Tisdale JF*. Myelodysplastic syndrome unrelated to lentiviral vector in apatient treated with gene therapy for sickle cell disease. Blood Adv. 2020 May 12;4(9):2058-2063.
5. Uchida N*, Hsieh MM, Raines L, Haro-Mora JJ, Demirci S, Bonifacino AC, Krouse AE, Metzger ME,
Donahue RE, Tisdale JF. Development of a forward-oriented therapeutic lentiviral vector for hemoglobin
disorders. Nat Commun. 2019 Oct 2;10(1):4479.

38

Hematopoietic stem cell gene therapy with a lentiviral genedeliveryNaoya Uchida
The Institute of Medical Science, The University of Tokyo, Japan

Hematopoietic stem cell (HSC)-targeted gene therapy is curative for various hereditary diseases,
including immunodeficiencies, hemoglobinopathies, congenital cytopenia, and metabolic
diseases. HSCs reconstitute peripheral blood for life due to their self-renewal and multipotency
specific for hematopoietic lineages; therefore, a replacement or repair of pathogenic mutations/deletions in HSCs allows for one-time cure of genetic diseases. A human immunodeficiency virus
type-1 (HIV-1)-based lentiviral vector system has been developed to deliver a normal or therapeuticgene to the target cell genome, and lentiviral integration can allow for long-term therapeutic gene
expression in HSCs. In preliminary HSC gene therapy trials in immunodeficiencies, a γ-retroviral
vector system was used for a therapeutic gene delivery; however, hematological malignancies
were developed due to insertional mutagenesis (Howe SJ. J Clin Invest. 2008). The γ -retroviral
vector system is generated from murine ‘leukemia’ virus (likely enhancing cell expansion), whichfavor integration into transcription start sites (near to a promoter) in activated genes, and if theγ -retroviral vector is integrated into an oncogene, the oncogene expression can increase by
the viral enhancer in the long terminal repeat (LTR), thereby inducing leukemia (Wu X. Science.
2003). In contrast, a new generation of lentiviral vector system has a minimal risk of leukemia
development, since this vector was generated from human ‘immunodeficiency’ virus (likely reducing
cell expansion), which are more equally integrated into a coding region in activated genes, andthe viral enhancer is removed from the LTR to produce self-inactivation. The HSC gene therapy
trials with lentiviral transduction result in phenotypic correction in 80-90% patients with various
diseases, and no insertional mutagenesis was observed for more than 200 patients (Eichler F. N
Engl J Med. 2017, Cavazzana M. Nat Rev Drug Discov. 2019, Kohn DB. Nat Med. 2020, Kohn DB.
N Engl J Med. 2021). Recently, 2 cases of acute myeloid leukemia were reported following an HSC
gene therapy in sickle cell disease (SCD) (Leonard A. Mol Ther. 2021). The lentiviral vector was
not integrated into leukemia cells in the first patient; however, in the second patient, the lentiviral
integration was detected within the VAMP4 gene in leukemia cells. The VAMP4 is not related tooncogenes, and it was not overexpressed in leukemia cells. In addition, patients with SCD have arisk of myeloid malignancies in their natural history as well as post-transplantation. Therefore, thisleukemia development is thought to be caused by disease status and/or conditioning instead oflentiviral integration. In conclusion, HSC gene therapies should improve the outlook for patientswith genetic diseases.

39

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Christopher Dott
Address (Affiliation)

Vice President Clinical Development, Orchard
Therapeutics Ltd.

Field of Research

Gene Therapy

Education
1974-1977 Queen Mary College, London University 			1980-1984 Royal Free Hospital, School of Medicine, University of London

BSc. Biology
Ph. D. Biochemistry

Professional Experience
1985-1988
Senior Clinical Research Associate G D Searle Ltd , UK
1988-1993
Clinical Research Manager, SmithKline Beecham, UK
1993-1999
Director Medical and Regulatory Affairs, Speywood Pharmaceuticals, UK
1999-2005
International Project Director, Ipsen Ltd, UK
2005-2006
Senior Director Clinical Affairs, Inamed, UK
2006-2018
Principle Consultant, CSD Pharma Consulting Ltd UK
2018 -present Vice President Clinical Development, Orchard Therapeutics Ltd. UK
Recent Related Publications (5 Papers)
1. Ferrua F, Cicalese MP, Galimberti S, Scaramuzza S, Giannelli S, Pajno R, Dionisio F, Biasco L, CastielloMC, Casiraghi M, Facchini M, Finocchi A, Metin A, Orange JS, Albert MH, Petrescu C, Bosticardo M, Villa
A, Dott C, vanRossem K, Valsecchi MG, Ciceri F, Roncarolo MG, Naldini L, Aiuti A. Safety and clinicalbenefit of lentiviral hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Blood 2015;
126;259 [ASH 2015]
2. Ferrua F, Cicalese MP, Galimberti S,  Giannelli S, Dionisio F, Bernardo ME, Migliavacca M, Barzaghi F,
Assanelli A, Scaramuzza S, Brigida I, Salerio F, Pajno R, Castiello MC, Casiraghi M, Facchini M, Fossati C,
Finocchi A, Metin A, Orange JS, Albert MH, Petrescu C, Xhafa M, Pesce F, Bosticardo M, Villa A, DottC, van Rossem K, Valsecchi MG, Ciceri F, Roncarolo MG, Naldini L, Aiuti A : Safety and clinical benefitof lentiviral hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome: the TIGET-WAS clinical
trial. ESID 2016
3. Ferrua F, Cicalese MP, Galimberti S,  Giannelli S, Dionisio F, Bernardo ME, Migliavacca M, Barzaghi F,
Assanelli A, Scaramuzza S, Brigida I, Salerio F, Pajno R, Castiello MC, Casiraghi M, Facchini M, Fossati C,
Finocchi A, Metin A, Orange JS, Albert MH, Petrescu C, Xhafa M, Pesce F, Bosticardo M, Villa A, Dott C,
van Rossem K, Valsecchi MG, Ciceri F, Roncarolo MG, Naldini L, Aiuti A. TIGET-WAS Phase I/II Clinical
Trial: Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich
Syndrome. XLP-WAS 2016 Symposium London 26-27 September 201640

Orchard Therapeutics and its Gene Therapy Programs
Christopher DottOrchard Therapeutics Ltd.

At Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe
diseases. We aim to do this by discovering, developing and commercializing new treatments thattap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, apatient’s own blood stem cells are genetically modified outside of the body and then reinserted,with the goal of correcting the underlying cause of disease in a single treatment.
In 2018, the company acquired GSK’s rare disease gene therapy portfolio, which originated froma pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy
in Milan, Italy. Today, Orchard has a deep pipeline spanning pre-clinical, clinical and commercial
stage HSC gene therapies designed to address serious diseases where the burden is immense
for patients, families and society and current treatment options are limited or do not exist.
Orchard are active in the primary immunodeficiencies and inherited neurometabolic disorders
fields. The primary immunodeficiency disorders (PIDs) cover adenosine deaminase severe
combined immunodeficiency (ADA-SCID) and Wiskott-Aldrich Syndrome (WAS). Within the ADASCID area Orchard have the first ex-vivo commercial product, Strimvelis®. As this product does
not have a cryopreserved formulation patients can only be treated in Milan, Italy where the productwas developed. WAS will be the second PID to be submitted for registration in the EU in early2022. The results from the WAS program show pronounced reductions in the clinical symptomsof the disease such as severe infections and bleeds and restoration of the defective protein in the
haemopoietic cells. Orchard also had its first inherited neurometabolic product approved in the
EU in December 2020 for the treatment of metachromatic leukodystrophy disease (MLD) which iscalled Libmeldy®. Libmeldy is used in children with MLD who have mutations in the arylsulfatase A
gene. It is given to those with late infantile or early juvenile forms of the disease who have not yet
developed symptoms and those with early juvenile MLD who have initial symptoms but can stillwalk independently and have not yet developed mental deterioration. Subjects have been followed
up for up to 11years in this program with no serious adverse events related to the product. The
pipeline of products at Orchard is currently focused on a number of other rare diseases suchas Mucopolysaccharidosis type I (Hurlers) and Mucopolysaccharidosis type IIIa also known as
Sanfilippo syndrome. Preclinical development work is ongoing is other larger indications such as
Crohn’s Diseases and Frontotemporal dementia.

41

Memo

Special lecture-Abstract & Curriculum Vitae-

12th Conference of International Collaborative Forum for Gene Therapy of Genetic Diseases

Aiuti Alessandro
Address (Affiliation)

Full professor of Pediatrics, “Vita-Salute San Raffaele”
University School of Medicine, Milan, Italy
Deputy Director Clinical Research and Head of Unit, San
Raffaele Telethon Institute for Gene Therapy, Milan, Italy
Chief of Clinic, Pediatric Immunohematology Unit, San
Raffaele Hospital, Milan, Italy

Field of Research-Gene transfer into human hematopoietic stem/progenitor
cells using retroviral and lentiviral vectors.
-Safety and efficacy of hematopoietic stem cell gene therapy forinherited disorders (ADA, WAS, MLD, MPSI, CGD).
-Study of dynamics and fate of human hematopoietic stem
cells after gene therapy.
-Genetic and immunological characterization of primary
immunodeficiencies due to unknown genetic defect.

Education
School of Medicine, University of Rome “La Sapienza”
School of Medicine, University of Milan

MD 1990, PhD 1996
National Board (Hematology) 1998

Professional Experience
1997-2000	Research Scientist, Telethon Foundation, Rome, Italy
2000-2007
MD Research Scientist, Scientific Institute H.S. Raffaele, Milan, Italy
2000-2007	Haematologist, Pediatric Clinical Research Unit, SR-TIGET, Scientific Institute H.S. Raffaele, Milan,
Italy
2003-2007
Head of Research Unit, SR-TIGET, Scientific Institute H.S. Raffaele, Milan, Italy
2004-2007	Member of the Committee for the Appointment and Promotions, Scientific Institute H.S. Raffaele,
Milan, Italy
2004-2010	Temporary assignment of Professorship, Course of “Molecular Pediatrics”, School of Medicine, “VitaSalute” San Raffaele University, Milan, Italy
2007-present	Head of Unit. Pathogenesis and therapy of primary immunodeficiencies, SR-TIGET, Scientific Institute
H.S. Raffaele, Milan, Italy
2007-2014
Haematologist, Pediatric Immunohematology Unit, San Raffaele Hospital, Milan, Italy
2007-10/2014 Associate Professor of Pediatrics, University of Roma Tor Vergata, Rome, Italy
2009-present Coordinator of Clinical Research, SR-TIGET, Scientific Institute H.S. Raffaele, Milan, Italy
2010-2013	Head, Gene Therapy Unit, Department of Pediatrics, University of Rome “Tor Vergata”, Bambino GesùPediatric Hospital, Rome, Italy
2011-2014	Head, Primary Immunodeficiencies (PID) outpatients’ clinic, Department of Pediatrics, University ofRome “Tor Vergata”, Bambino Gesù Pediatric Hospital, Rome, Italy
05/2011-present Head, Clinical Research Unit, SR-TIGET, Scientific Institute H.S. Raffaele, Milan, Italy
11/2014-present		 Director, Pediatric Immunohematology Unit, San Raffaele Hospital, Milan, Italy
01/2016-present Full Professor of Pediatrics, “Vita-Salute” San Raffaele University, Milan, Italy
11/2016-present Director, Pediatrics Residency Program, “Vita-Salute” San Raffaele University, Milan, Italy
04/2017-present Deputy Director Clinical Research, SR-TIGET, Scientific Institute H.S. Raffaele, Milan, Italy
Recent Related Publications (5 Papers)
1. Ferrua F, Cicalese MP, Aiuti A, et al. (2019) . Lentiviral haematopoietic stem/progenitor cell gene therapy for thetreatment of Wiskott-Aldrich syndrome: interim results of a non-randomized, open-label, phase 1/2 clinical study.
Lancet Hematology. 6: e239-e253. Epub 2019 April 10
2. Scala S, Basso-Ricci L, Aiuti A, et al. (2018). Dynamics of hematopoietic stem/progenitor cells after autologoustransplantation in humans. Nat Med. 24:1683-1690. Epub 2018 Oct 1.
3. Ferrari G, Thrasher AJ, Aiuti A. (2021). Gene therapy using haematopoietic stem and progenitor cells. Nat Rev
Genet. 22: 216-234. Epub 2020 Dec 10.
4. G entner B, Tucci F, Aiuti A, et al.; MPSI Study Group.(2021). Hematopoietic Stem- and Progenitor-Cell Gene
Therapy for Hurler Syndrome. N Engl J Med. 385:1929-1940.
5. Fumagalli F, Calbi V, Aiuti A, et al. (2021). Lentiviral haematopoietic stem-cell gene therapy for early-onset
metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded
access. The Lancet. In press.

44

Hematopoietic stem cell gene therapy for inborn errors of
immunity and metabolism
Aiuti Alessandro
San Raffaele Telethon Institute for Gene Therapy, Milan, Italy

Gene therapy using haematopoietic stem and progenitor cell (HSPC) has been shown an effective
treatment for inborn errors of immunity, such as ADA-SCID, SCID-X1, chronic granulomatous
disease. Several studies have shown engineered HSPCs can also be used to cross-correct
non-haematopoietic cells in neurodegenerative metabolic diseases such as metachromatic
leukodystrophy and mucopolysaccharidosis type I. In Europe, medicinal products based on
autologous HSPCs have been approved for clinical use and others are under clinical development.
I will discuss the most recent advances and challenges in HSPC gene therapy.

45

Memo

Acknowledgments
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