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February 2018, 14th
FEATURE STORY ● Advances in spinal muscular atrophy therapeutics RARE DISEASES ● Strategies for care quality improvement in Cystic Fibrosis ● The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy GENE THERAPY ● Single intramuscular injection of AAV-shRNA reduces DNM2 and prevents myotubular myopathy in mice CLINICAL TRIALS ● Genethon starts a clinical trial to test a gene therapy treatment for Crigler-Najjar Syndrome ● BioMarin presents interim data of phase I/II study of BMN 250 for treatment of Sanfilippo B Syndrome ● ArmaGen’s AGT-181 demonstrates neurocognitive benefit in children with severe MPS I ●Abeona Therapeutics reports top-line data from phase I/II gene therapy trial in MPS IIIA INDUSTRIAL LANDSCAPE - AGREEMENTS ● Vertex: FDA Approves Symdeko™ (tezacaftor/ivacaftor and ivacaftor) for CF MISCELLANEOUS ● Paediatric genomics: diagnosing rare disease in children

February 2018, 14th

FEATURE STORY

● Advances in spinal muscular atrophy therapeutics

RARE DISEASES

● Strategies for care quality improvement in Cystic Fibrosis

● The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy

GENE THERAPY

● Single intramuscular injection of AAV-shRNA reduces DNM2 and prevents myotubular myopathy in mice

CLINICAL TRIALS

● Genethon starts a clinical trial to test a gene therapy treatment for Crigler-Najjar Syndrome

● BioMarin presents interim data of phase I/II study of BMN 250 for treatment of Sanfilippo B Syndrome

● ArmaGen’s AGT-181 demonstrates neurocognitive benefit in children with severe MPS I

●Abeona Therapeutics reports top-line data from phase I/II gene therapy trial in MPS IIIA

INDUSTRIAL LANDSCAPE - AGREEMENTS

● Vertex: FDA Approves Symdeko™ (tezacaftor/ivacaftor and ivacaftor) for CF

MISCELLANEOUS

● Paediatric genomics: diagnosing rare disease in children

FEATURE STORY

Advances in spinal muscular atrophy therapeutics

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. The review appeared in February 05th online issue Ther Adv Neurol Disord .

Related Informations/Publications

• Nat Rev Neurol . 2018 Feb 9. Advances in therapy for spinal muscular atrophy: promises and challenges.
Groen EJN, Talbot K, Gillingwater TH. University of Edinburgh, Edinburgh, UK. Link : Abstract .
• Front Mo l Neurosci . 2017 Dec 7;10:405. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. Tosolini AP, Sleigh JN. University College London, UK. Link : Abstract . Full Tex t. -• JAN 2018 : AveXis Announces Expanded Clinical Development Program for AVXS-101 in Spinal Muscular Atrophy Results / Comments : In addition to the ongoing pivotal trial in SMA Type 1 (STR1VE) and the ongoing Phase 1 tri. l in SMA Type 2 (STRONG), the company plans to initiate three studies to further evaluate AVXS-101. Link : Press Release .
• JUN 2017 : Nusinersen Approved in the European Union as First Treatment for Spinal Muscular Atrophy.
Link : Press Release .

RARE DISEASES

Strategies for care quality improvement
in Cystic Fibrosis

Cystic fibrosis (CF) is a “model” of international collaboration for therapeutic research, social science research, development of international guidelines and care management all at once, because of its characteristics: a genetic disease which is progressive, chronic and multisystemic, with a prevailing impairment of the respiratory function, and also a “rare disease”, albeit the most common of “rare diseases” in Caucasian populations. Globally, the 1980s were marked by the first successful pulmonary transplant on cystic fibrosis patients and the discovery of the CFTR gene. “Resignation” gave way to hope, based on the acceleration of research efforts shown by the simultaneous increase of articles on this disease. In France, a greater interest for this disease from medical teams, a better care management by multidisciplinary teams in specialized health centres and the creation of the National Cystic Fibrosis Observatory (1992) marked this turning point.
The review appeared in February 08th online issue of Orphanet J Rare Dis .

Related informations/publications

• Am J Physiol Lung Cell Mol Physiol . 2017 Dec 14. Personalized Medicine in CF: From Modulator Development to Therapy for Cystic Fibrosis Patients with Rare CFTR Mutations. Harutyunyan M et al. Cincinnati Children's Hospital Medical Center, USA. Results / Comments : This review provides an overview of recent advances in the development of CFTR modulators, including those approved for clinical use.
Link : Abstract .
• London: National Institute for Health and Care Excellence (UK); 2017 Oct. Cystic Fibrosis: Diagnosis and management. National Guideline Alliance (UK).
Link : Abstract . Full Text

The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy

Duchenne muscular dystropy (DMD) is a lethal, X-linked muscle-wasting disease caused by the lack of dystrophin. A few years after the identification of the dystrophin gene, a ubiquitously expressed transcript with high homology to dystrophin was identified leading to the postulate that utrophin might be an effective surrogate to compensate for the lack of dystrophin in dystrophic muscles. British investigators reviewed the utrophin gene, its regulation, the organisation of the corresponding protein and its dynamic expression pattern in comparison with dystrophin. In view of the evidence that utrophin act an efficient substitute to dystrophin to prevent the pathology, they describe the therapeutic approaches to modulate utrophin expression. They review the current status in the development of ezutromid, the first small utrophin modulator drug currently tested in DMD patients. The review appeared in February 08th online issue of Exp Opin Orphan Drugs .

Related informations/publications

• JAN 2018: Summit presents interim results from the open-label Phase 2 proof of concept clinical trial, PhaseOut DMD. PhaseOut DMD is evaluating the utrophin modulator ezutromid in patients with Duchenne muscular dystrophy. Results / Comments: Increase in Utrophin Protein Expression Observed.
Link: Press Release .
• N at Rev Neurol. 2017 Nov;13(11):647-661. Genome engineering: a new approach to gene therapy for neuromuscular disorders. Nelson CE et al. Duke University, Durham, North Carolina 27708-0281, USA.
Link : Abstract .
• Mol Ther Methods Clin Dev . 2017 Jul 27;6:216-230. A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy. Hakim CH et al. University of Missouri, Columbia, MO 65212, USA. -Link : Abstract . Full Text .

GENE THERAPY

Single intramuscular injection of AAV-shRNA reduces DNM2 and prevents myotubular myopathy in mice

Myotubular myopathy , or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the Myotubularin (MTM1) gene cause myotubular myopathy and no specific curative treatment is available. We previously found that Dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, while its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice. French investigators recently proposed a novel approach targeting Dnm2 mRNA. They screened and validated in vitro and in vivo several shRNA sequences that efficiently target Dnm2 mRNA. A single intramuscular injection of AAV-shDnm2 resulted in long-term reduction of DNM2 protein level and restored muscle force, mass, histology and myofiber ultrastructure, and prevented molecular defects linked to the disease. The results appeared in February 13th online issue of Mol Ther .

Related Informations / Publications

• J Neuropathol Exp Neurol . 2018 Feb 2. Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice. Danièle N et al. R&D Department, Genethon, Evry, FR. Results / Comments : Strategies aiming at increasing MTMR2 expression levels in skeletal muscle may be beneficial in the treatment of myotubular myopathy. Link : Abstract .
• SEP 2017 : Audentes Therapeutics Announces Dosing of First Patient in ASPIRO, a Phase 1/2 Clinical Trial of AT132 for the Treatment of X-Linked Myotubular Myopathy ( NCT03199469 ). Link : PRnewswire .

CLINICAL TRIALS

Genethon starts a clinical trial to test a gene therapy treatment for Crigler-Najjar Syndrome

Généthon , a laboratory created by AFM-Téléthon, said on February 12th that it starts a European phase I/II clinical trial to test a treatment for Crigler-Najjar Syndrome, a rare liver disease. The trial, sponsored by Généthon, will include 17 patients in four centres in Europe, and will assess safety and therapeutic efficacy of the gene therapy product developed by Généthon. Crigler-Najjar Syndrome is a rare genetic liver disease (incidence around 1/1 000 000 births) associated with the abnormal accumulation of bilirubin — a yellow pigment produced by the liver — in all the body’s tissues, particularly the brain tissues. This hyperbilirubinaemia is caused by a deficiency in UGT1A1, the enzyme that converts bilirubin into an eliminable substance. When this enzyme does not work, bilirubin levels build up, leading to severe chronic icterus (jaundice) and becoming toxic to the brain.
For further info .

Related Informations / Publications

• FEB 2018 : Audentes Therapeutics Announces Dosing of First Patient in VALENS, a Phase 1/2 Clinical Trial of AT342 for the treatment of Crigler-Najjar Syndrome. Results / Comments : Audentes expects preliminary data from VALENS to be available in the second quarter of 2018. Link : Press Release .
• Hum Gene The r. 2014 Sep;25(9):844-55. Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler-Najjar Syndrome. Bortolussi G et al. International Centre for Genetic Engineering and Biotechnology , 34149 Trieste, Italy.
Results / Comments : Data support the concept that liver is the best organ for efficient and long-term Crigler-Najjar Syndrome type I gene therapy. Link : Abstract . Full Text .

BioMarin presents interim data of phase I/II study of BMN 250 for treatment of Sanfilippo B Syndrome

Biomarin Pharmaceuticals announced on February 07th that it presented interim data from a phase I/II trial for BMN 250, an investigational enzyme replacement therapy using a novel fusion of recombinant human alpha-N-acetylglucosaminidase (NAGLU) with a peptide derived from insulin-like growth factor 2 (IGF2), for the treatment of Sanfilippo B syndrome or mucopolysaccharidosis IIIB at WORLDSymposium 2018. Discovered by BioMarin, BMN 250 is being studied in a multicenter, international clinical trial evaluating safety and tolerability, as well as cognitive function of patients with Sanfilippo B receiving BMN 250.
For further info

Related Informations / Publication

• Metab Brain Dis . 2018 Feb;33(1):1-10. How close are we to therapies for Sanfilippo disease? Gaffke L et al. University of Gdańsk, Poland. Link : Abstract . Full Text .
• Lancet Neuro l. 2017 Sep;16(9):712-720. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Tardieu M et al. Université Paris Sud and Assistance Publique-Hôpitaux de Paris, FR. Link : Abstract.
• SEP 2017 : BioMarin Presents Interim Data of Phase 1/2 Study of BMN 250 for Treatment of Sanfilippo B Syndrome (MPS IIIB) at 13th International Congress of Inborn Errors of Metabolism (ICIEM) 2017.
Results / Comments: Preliminary biomarker and liver size data show marked decreases; early cognitive effects encouraging, pending more mature data. Link: Press Release .

ArmaGen’s AGT-181 demonstrates neurocognitive benefit in children with severe MPS I

Armagen , a privately held biotechnology company focused on developing groundbreaking therapies to treat severe neurological disorders, reported on February 08th full 52-week results from a Phase 2 proof-of-concept study with AGT-181, the company’s investigational therapy for the treatment of mucopolysaccharidosis type I, or MPS I (also known as Hurler, Hurler-Scheie and Scheie syndromes). Data presented at the 14th Annual WORLDSymposium in San Diego, California, suggest that AGT-181 stabilized the neurocognitive development quotient (DQ) in patients with severe MPS I. The data validate previous findings that demonstrated the ability of ArmaGen’s proprietary drug delivery technology to transport biopharmaceuticals across the blood-brain barrier (BBB) and provide therapeutic benefit to patients with severe MPS I. For further info .

Related Informations / Publications

• Eur J Pharm Biopharm . 2018 Jan;122:158-166. Gene editing of MPS I human fibroblasts by co-delivery of a CRISPR/Cas9 plasmid and a donor oligonucleotide using nanoemulsions as nonviral carriers. Schuh RS et al. Hospital de Clinicas de Porto Alegre, BRA. Link : Abstract .
• J Inherit Metab Dis. 2017 Jul;40(4):543-554. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. Penati R et al. IRCCS San Raffaele Scientific Institute, Milan, Italy. Link : Abstract. Full Tex t.
• FEB 2017 : Armagen Reports Preliminary Evidence of Cognitive Improvement in Children with Hurler Syndrome (MPS I) Treated with AGT-181. Link: Press Release .

Abeona Therapeutics reports top-line data from phase I/II gene therapy trial in MPS IIIA

Abeona Therapeutics , a leading clinical-stage biopharmaceutical company focused on developing novel cell and gene therapies for life-threatening rare genetic diseases, announced on February 08th updated clinical data from the ongoing phase I/II trial for ABO-102 (AAV-SGSH), the company’s investigational gene therapy for the treatment of Sanfilippo syndrome Type A ( mucopolysaccharidosis type IIIA ), a rare autosomal-recessive lysosomal storage disease. The results demonstrate robust and durable clinical effects achieved throughout various timepoints post-administration. To date, 10 patients have been dosed with a single intravenous injection of ABO-102. Results were reported during the WORLDSymposium for Lysosomal Diseases being held this week in San Diego, CA. For further info .

Related Informations / Publications

• FEB 2018 : Lysogene to Present Five Year Clinical Data in MPS IIIA at the 14th Annual WORLDSymposium Results / Comments : Design, baseline characteristics, and early findings of the MPS IIIA clinical observational study in 23 patients. Link : Press Release .
• Mol Genet Metab. 2017 Dec;122S:25-34. Treatment of brain disease in the mucopolysaccharidoses. Scarpa M et al. Center for Rare Diseases, Wiesbaden, Germany. Link : Abstract. Full Text .
• MAY 2017 : Abeona Therapeutics Announces Top-Line Data for ABO-102 Phase 1/2 MPS IIIA Gene Therapy Trial at ASGCT. Results / Comments : ABO-102 well-tolerated in six subjects through 1100 days follow up with no Serious Adverse Events. Link : Press Release .

INDUSTRIAL LANDSCAPE AND
AGREEMENTS

Vertex: FDA Approves Symdeko™ (tezacaftor/ivacaftor and ivacaftor) for CF

Vertex Pharmaceuticals announced on February 12th that the FDA approved Symdeko™ (tezacaftor/ivacaftor and ivacaftor) for treating the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or who have at least one mutation that is responsive to tezacaftor/ivacaftor. Symdeko™ is Vertex's third medicine approved to treat the underlying cause of CF. Vertex is ready to launch Symdeko™ and will begin shipping it to pharmacies in the United States this week.
For further info .

Related Informations / Publications

• FEB 2018 : Vertex Selects Two Next-Generation Correctors, VX-659 and VX-445, to Advance into Phase 3 Development as Part of Two Different Triple Combination Regimens for People with Cystic Fibrosis
Link: Press Release .
• JAN 2018 : EU Approval for ORKAMBI (lumacaftor/ivacaftor) in Children with Cystic Fibrosis Ages 6-11 with Two Copies of the F508del Mutation. Link: Press Release .
• DEC 2017 : Vertex and CRISPR Therapeutics to Co-Develop and Co-Commercialize CTX001 as CRISPR/Cas9 Gene Edited Treatment for Sickle Cell Disease and β-Thalassemia. Results /Comments: Clinical Trial Application for CTX001 submitted in Europe to support initiation of Phase 1/2 clinical study in β-thalassemia in 2018 Link: Press Release .

MISCELLANEOUS

Paediatric genomics:
diagnosing rare disease in children

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease.
The review appeared in February 05th online issue of Nat Rev Genet .

Related Informations / Publications

• Rare Dis . 2015 Sep 16;3(1):e1083145: Rare disease diagnosis: A review of web search, social media and large-scale data-mining approaches. Svenstrup D et al. Bispebjerg Hospital ; Copenhagen, Denmark
Link: Full Text .

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