Many rare diseases are inherited disorders. Amongst these, Inborn Errors of Metabolism (IEM) represent a major category of more than 500 individual diseases, often caused by defective enzymes leading to an insufficient or absent conversion of substrates into products. Toxic substances accumulate upstream resulting in a reduction in downstream compounds or abnormal alternative substrate metabolism [2]. Lysosomal storage diseases are one major group that exemplifies classic IEM. However, IEM do not always fall neatly into disease categories, as they may present with many symptoms and affect different organs at different ages based upon disease pathophysiology. Many IEM present clinically with neurologic manifestations that includes cognitive impairment, seizures and movement disorders [3]. IEM are traditionally considered pediatric diseases, but there is increasing awareness of adult onset IEM that necessitate diagnoses [4].

Many inherited or genetically based rare diseases include diagnoses of epileptic encephalopathies. These diagnoses are heterogeneous and can be caused by both de-novo mutations and recessive mutations, in addition to chromosomal abnormalities [5]. Epileptic seizures damage neuronal function, but seizure-independent mechanisms may also contribute to cognitive impairment. In the latter case, affected individuals would be unlikely to respond to conventional antiepileptic therapies [5].

Role of Diagnosis

Early diagnosis of inborn errors leading to early treatment to prevent long-term neurologic damage is important, but too frequently, diagnosis of involves a tortuous and lengthy process with many tests, some considerably invasive, such as biopsies. Diagnosis is important for prognostic implications, disease management and treatment optimization in cases where therapies (even if not curative) are available. Recognition of characteristic phenotypes is important in diagnosis; with advances in knowledge and technology, targeted genetic testing may allow diagnosis in a larger number of children. Gene panels appears to have utility in diagnosis of patients with early-onset epilepsy, but diagnosis at the molecular level using gene panels is not yet standard practice [6], and may be impacted by both technological limitations and cost. Additionally, -phenotype may evolve over the life cycle, as it is dependent upon different metabolic pathways that are developmentally impacted. The diagnosis of an adult onset IEM, vs. evolving pathology of earlier onset IEM is an evolving field [4].

Early diagnosis enables accurate study of historical presentation, and a better understanding of phenotype: genotype correlation, a very useful tool for accelerating targeted novel therapies. As whole exon sequencing (WES) and whole genome sequencing (WGS) become more widely available, collaborations between clinicians, researchers and affected families through international databases will enable new discoveries and vastly improve the diagnostic process [5].

Current Therapeutic Approaches

Treatment for IEMs includes enzyme replacement therapy (ERT), substrate reduction therapies, dietary modification and hematopoietic stem cell transplant (HSCT). The former has significant efficacy limitations due to the inability to cross the blood-brain-barrier and the mounting of an immune response to the enzyme replacement [7]. HSCT shows promise in pre-symptomatic juvenile patients with sufficiently long therapeutic window.

For a majority of genetically based epilepsies, disease specific treatments are not available. Directed therapies targeting specific gene defect, abnormal protein or dysfunctional pathway are in development. Comprehensive treatment goals include seizure control as well as improving developmental outcome and associated co-morbidities. Novel approaches include stem cell programs to test novel compounds and translation to animal and clinical studies as well as gene therapies.

Gene Therapy

The feasibility and potential clinical benefit of gene therapy has been documented for a wide range of genetic diseases, including hematological, immunological, ocular, neurodegenerative and metabolic disorders [8, 9]. For rare diseases, gene therapy holds the most promise for monogenic disorders with caused by a mutation in a single gene. Two common approaches to gene therapy include ex vivo modification of cells or direct in vivo infusion. The latter suffers from the potential of inappropriate tissue/cell targeting, immunogenicity to the vector, and off-target transgene-related toxicities. The ex-vivo model requires cell manipulation before infusing back into the patient which can be a significant manufacturing challenge. Despite the many challenges, both ex vivo and in vivo approaches are yielding promising results in animal models of genetic disease.

Rare Diseases Forum Principles

Aims

The Rare Diseases Forum aims to advance the regulatory sciences for the diagnosis and treatment of inborn errors of metabolism and other genetically based rare diseases by providing an independent and neutral venue for ongoing multi-stakeholder dialogue. The objective of the Rare Diseases Forum is to facilitate the development of new therapeutics for rare diseases by advancing the regulatory science; maximizing efficiency through collaborations; and making use of innovation afforded by the 21st Century Cures Act, including totality of evidence, use of novel/innovative analytics, and efficient/rigorous evaluation of novel biotechnology.

Our work will facilitate making the best science-based decisions as our collective knowledge and experience with therapies for rare diseases advances. Once new drug candidates and therapeutic strategies are identified, their rapid, safe development is in the best interest of all stakeholders, most of all, the patients [10]. The Rare Diseases Forum provides a platform for careful and ongoing deliberation on issues of common interest and concern. We ensure neutrality and objectivity through representation and active engagement of scientific experts from all stakeholder groups, including academia, industry, patient representatives, and regulatory agencies in a non-competitive and safe environment. This structure allows the whole field to benefit from valuable lessons learned, and breaks down inefficiencies by increasing clarity and standardization, and decreasing uncertainty.

Context

The US, EU and many other regulatory agencies recognize the term “rare disease” and have put in place incentives to stimulate development of therapeutics (frequently referred to as “orphan drugs”) [11]. Regulatory incentives have increased orphan drug designations and approvals [12, 13]; yet less than 500 treatments are approved for the more than identified 7,000 rare diseases. Top among the challenges in therapeutic development include the small number of, and heterogeneity among, patients, combined with lack of understanding of disease physiopathology. Regulatory needs include defining endpoints, identifying and validating biomarkers.

Strimvelis is the first ex-vivo gene therapy approved (in the EU only) for the treatment of ADA- SCID for patients with no suitable bone-marrow transplant donor [14, 15]. Following initial successes, industry is now enthusiastic about tackling the formidable challenges and the regulatory framework for the delivery of complex, individualized cell and gene therapy [16]. Some of the early development paths suffered from inefficiencies in product development and problematic translation from academic to industry settings [17]. Several examples illustrate the challenges and benefits of academic and industry collaboration [8]. Bringing in trans-atlantics regulatory expertise and patient centered research context promises to further catalyze and facilitate the process as gene and modified cell therapy approaches find their place among more familiar concepts such as medicinal products, biotherapeutics, and transplantable organs.

Action Plan

The Rare Diseases Forum operates in accordance with The Forum's guiding principles, which include neutrality and independence; transparency and accessibility; inclusiveness; collaboration; and efficiency and productivity.

The Rare Diseases Forum is led by a Steering Committee and managed by Forum staff. Throughout the year, the Rare Diseases Forum convenes working group conference calls, email/web-based communication, and in-person meetings and workshops as needed. Project experts are recruited from academia, community, federal agencies, professional societies, and industry.

The Rare Diseases Forum 1 was held on October 17 at the Carnegie Endowment for International Peace in Washington DC. 114 people attended the Forum. 98 attended in person, and 16 people registered for the webcast.

Project members are recruited from academia, community, federal agencies, professional societies, and industry. The project is open to all pharmaceutical, biotech and diagnostic companies involved in relevant clinical research. 

Working groups will be a major component of the Rare Diseases Forum and will be developed to address the above work streams and any other priority areas identified by both the steering committee and the Rare Diseases Forum members. Expected outcomes of the working groups include recommendations, position papers, reports, manuscripts for submission to peer- reviewed journals, and presentations at conferences.

Leadership

The Steering Committee provides leadership, strategic direction and guidance in identifying the main questions that will be addressed as well as recommend individual experts from academia, industry, government, and community to ensure adequate representation of expertise. The Forum rotates the steering committee membership to ensure leadership opportunities to more individuals, especially those from industry. The industry co-chair position will be rotated on a two-year basis.

 

Membership

The Rare Diseases Forum membership is by invitation only. Project members are recruited from academia, community, federal agencies, professional societies, and industry. Membership is open to scientific experts from pharmaceutical, biotech, and diagnostic industry organizations committed to and actively engaged in research and development in this field.

Participation from industry is conditional on an annual sponsorship contribution.  Industry members will be acknowledged as Rare Diseases Forum sponsors. Sponsorship includes participation in-person meetings, working groups, webinars, remote attendance, and project updates. Non-sponsoring industry will have access to information published on the Rare Diseases Forum’s website. Annual contributions from non-industry organizations are encouraged. Members from pharmaceutical, biotech, device, and diagnostic industry organizations must be scientific or regulatory experts actively engaged in research and development in the field of Rare Diseases. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed Rare Diseases Forum members meetings, but will be allowed to participate in any public meetings the Forum sponsors.

The Forum does not cover any honoraria or provides items of value (gifts) to any speakers or attendees. Membership cannot be combined/divided for participation in different disease specific projects at the Forum.

 

References
1.            Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L. Patient- Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2017;20(7):838-55.

2.            Vernon HJ. Inborn Errors of Metabolism: Advances in Diagnosis and Therapy. JAMA Pediatr. 2015;169(8):778-82.

3.            Saudubray JM, Garcia-Cazorla A. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am. 2018;65(2):179-208.

4.            Saudubray JM, Mochel F. The phenotype of adult versus pediatric patients with inborn errors of metabolism. J Inherit Metab Dis. 2018.

5.            McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304-16.

6.            Trump N, McTague A, Brittain H, Papandreou A, Meyer E, Ngoh A, et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet. 2016;53(5):310-7.

7.            Penati R, Fumagalli F, Calbi V, Bernardo ME, Aiuti A. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. J Inherit Metab Dis. 2017;40(4):543-54.

8.            Mavilio F. Developing gene and cell therapies for rare diseases: an opportunity for synergy between academia and industry. Gene Ther. 2017;24(9):590-2.

9.            Naldini L. Gene therapy returns to centre stage. Nature. 2015;526(7573):351-60.

10.          Baird LG, Banken R, Eichler HG, Kristensen FB, Lee DK, Lim JC, et al. Accelerated access to innovative medicines for patients in need. Clinical pharmacology and therapeutics. 2014;96(5):559-71.

11.          Richter T, Nestler-Parr S, Babela R, Khan ZM, Tesoro T, Molsen E, et al. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2015;18(6):906-14.

12.          Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, et al. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009;96(1):20-6.

13.          Haffner ME. Adopting orphan drugs--two dozen years of treating rare diseases. The New England journal of medicine. 2006;354(5):445-7.

14.          Stirnadel-Farrant H, Kudari M, Garman N, Imrie J, Chopra B, Giannelli S, et al. Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. Orphanet J Rare Dis. 2018;13(1):49.

15.          Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9(6):737-40.

16.          Smith DM, Culme-Seymour EJ, Mason C. Evolving Industry Partnerships and Investments in Cell and Gene Therapies. Cell Stem Cell. 2018;22(5):779.

17.          Bryant LM, Christopher DM, Giles AR, Hinderer C, Rodriguez JL, Smith JB, et al. Lessons learned from the clinical development and market authorization of Glybera. Hum Gene Ther Clin Dev. 2013;24(2):55-64.