Orphans without borders: personalized medicine and international collaboration in rare diseases

Administrator: Claudio Melo de Gusmao, US

MD Claudio Melo de Gusmao
Boston Children's Hospital
claudio.degusmao@childrens.harvard.edu
Clinical Protocol and Interim Outcomes of ASO trial in Ataxia-Telangiectasia (20 min)

Antisense oligonucleotide treatment of Ataxia Telangiectasia – interim trial results
We describe the identification, drug development and treatment of 2 patients with Ataxia Telangiectasia. The first patient was diagnosed after a positive finding on newborn screening. The screening was developed to identify potential cases of severe combined immune deficiency (SCID), but incidentally it reveals some cases of defective ATM functional status. The patient harbors biallelic mutations, one in particular (c.7865C>T) that creates a strong splice donor site leading to frameshift and premature translational termination. We describe the validation of the efficacy of a customized ASO to restore splicing and functional ATM activity and interim n-of-1 trial results. At the age of 2y9m, the patient started treatment in a research protocol. No severe symptomatic decline or adverse event has arisen as of current. The second patient has an identical mutation (c.7865C>T), which is biallelic in trans with c.829G>T. He was diagnosed clinically at age 2 years while living in Turkey. He is currently 4y 9m old and is expected to start treatment in November 2021. He will start treatment in the United States and then continue continue treatment through an international collaboration. 

MD Banu Anlar
Hacettepe University
banlar@hacettepe.edu.tr
Ataxia Telangiectasia as a model for networks on rare disorders (20 min)

Dr. Ibrahim Oncel
Clinical experience and interim data on the Turkish A-T center of excellence (10 min)

Rare disease centers of excellence: the Turkish perspective
Ataxia Telangiectasia is an orphan disease, affecting 1/100,000 people. It is characterized by severe combined immunodeficiency associated with predisposition to develop cancer and progressive cerebellar ataxia that leads to disability and premature death. Despite its status as an orphan disease, it is the most common cause of genetically inherited genetic ataxia in very young children. The speaker will provide an overview of the creation, establishment and advocacy of rare disease centers of excellence in Turkey, as well as patient-led foundation to support families caring for children with Ataxia Telangiectasia in Turkey. In addition, the speaker will discuss the genetic background of Ataxia-Telangiectasia in Turkey, emerging knowledge of the prevalence of an ASO-targetable mutation in the Turkish population and ongoing efforts at improving access to n-of-1 trials. The talk will facilitate the discussion about patient selection, transparency in identifying candidates and bioethical standards to allow equitable access to treatment.

MD Matthis Synofzik
Division of Translational Genomics of Neurodegenerative Diseases, University of Tubingen
matthis.synofzik@uni-tuebingen.de
European platform for n-of-1 therapies  (pre-recorded talk; 20 min)

1 Mutation 1 Medicine (1M1M): a European platform for n-of-1 ASO therapies
Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on ‘‘more common’’ RNDs, leaving a large share of genetic RND patients – in particular at childhood age – still without prospect of disease-modifying treatments. In response to this gap, the cross-European consortium “1Mutation 1 Medicine” (1M1M) systematically develops n-of-1 ASO treatment approaches targeting ultrarare or even private variants. Specifically, it has started to prepare a platform for the development and implementation of mutation-specific splice switching ASO therapies for RND patients. In this platform, generic process components of the n-of-1 ASO pipeline are bundled and optimized (e.g. ASO design and optimization, ASO preclinical efficacy, ASO n-of-1 outcome measures and trial design), complemented by target-specific steps where standard operating procedures are developed that allow to regulate quality standards and process flows also across the different ASOs and centers. Via this platform design, it will allow scalability of this approach from 1-2 to multiple RND patients alike. This talk will present this programme, and provide genetic, regulatory, and ethical perspectives for preparing these highly exciting n-of-1 ASO treatments, with a specific focus on the European context.

MD Timothy Yu
Boston Children's Hospital
timothy.yu@childrens.harvard.edu
Selection, development and collaboration for ASO trials in ultra-rare diseases  (pre-recorded talk, 20 min)

Exciting advances in technology are accelerating the pace of therapeutic development for neurogenetic disorders, even some previously considered too rare to support commercial investment. Antisense oligonucleotides (ASOs), the modality utilized by nusinersen for spinal muscular atrophy, are one of these technologies. Despite these advances, rare disease therapeutic developmentcontinues to be costly or unequally available across the globe. Dr. Yu will conclude the session devoted to individualized therapies by introducing the N of 1 collaborative, a new community effort devoted to the safe and just advancement of individualized medicine. The N=1 collaborative will work synergistically with academic medical centers, the OTS, n-Lorem, and other international efforts to tackle opportunities and challenges in this growing field developing and disseminating best practices, promoting institutional readiness, and facilitating data sharing. Through this activity, participants will learn which types of patients are most likely to benefit from individualized therapy, the importance of the type of mutation rather than the type of disease, strategies in navigating interactions with industry and foundations, the perspective of parents, and consider where this type of application could lead.