The typical paradigm is that new technologies in medicine transition from the laboratory (Bench) through several steps towards eventual use to treat patients (Bedside).  But clinical and genetic studies have a lot to teach us about dysferlinopathy and can inform research projects looking for new treatments.  This webinar included overviews of the clinical phenotype and genetics of dysferlinopathy, and also highlighted some of the findings of recent clinical studies, in particular the Clinical Outcome Study in Dysferlinopathy (COS), as well as large-scale sequencing studies that document the spectrum of mutations of the DYSF gene and carry implications about the role of the dysferlin protein in muscle biology.

Recent discoveries show how dysferlin deficiency affects cellular metabolism and how diet and exercise may affect the course of dysferlinopathy. Metabolic changes in skeletal muscle are a hallmark of several types of muscular dystrophy.  In vitro and in vivo studies of dysferlinopathy have identified metabolic effects are often distinct or at odds with observations from other types of muscular dystrophy.  This indicates that some metabolic changes may be unique to dysferlin deficiency rather than being caused by generic dystrophic processes.  This webinar included findings from metabolic studies on dysferlin-deficient muscle fibers, and the impact of dietary interventions on the phenotype of dysferlinopathy.

This webinar covered a variety of recent results across several topics related to dysferlin and dysferlinopathy – from research tools to big data analysis, to the latest insights on protein structure, to therapeutic strategies. Several laboratories presented findings that the Jain Foundation had been following with great interest, but which were not published yet.  We felt that sharing these results through this webinar (which can be thought of akin to a “late breaking developments” session at a scientific conference) would be extremely valuable to the entire dysferlin research community.

If you were unable to attend the webinar, but are interested in viewing the recording, please contact the Jain Foundation at admin@jain-foundation.org

Lisa Primiano
Scientific Program Manager

Ms. Primiano earned her M.S. degree in Human Genetics (Genetic Counseling Track) from VCU School of Medicine and her B.S. degree in Biology from the Massachusetts Institute of Technology. She contributes to the strategic direction of the Jain Foundation and works with the Scientific Advisory Board to develop and supervise a portfolio of dysferlinopathy research projects and patient programs.

Ms. Primiano has extensive experience in university technology transfer, helping to move promising inventions from the bench to the bedside. Prior to joining the Jain Foundation in 2021, she established the technical marketing program for the Office of Technology Management at Washington University in St. Louis. Previously, she served in various roles for the Office of Technology Licensing at Stanford University, including licensing, managing special projects and leading the technical marketing team. Before that, she was a Genetics Associate at Genzyme Genetics (now LabCorp) where she was responsible for coordinating genetic testing and analysis.

Summary: In protein chemistry, “structure determines function.”  Dysferlin is a rather challenging protein to study as it is a large protein with many folding domains (at least 10 have been identified so far), and it appears to have multiple functions and a number of binding partners.  Understanding the folding structure of dysferlin can help identify functions, as well as determine what changes to the amino acid sequence are pathogenic.  Several research groups have been studying the folding structure and interactions of dysferlin using a variety of techniques.  Although the folding structure and interactions of dysferlin aren’t yet completely understood, we think that there is a large amount of new data, which can serve to generate discussions, hypotheses, and collaborations in the research community.

Availability:
The Jackson Laboratory
Stock number: 012767
Strain information: http://jaxmice.jax.org/strain/012767.html
Phone: 800-422-MICE (800-422-6423)
610 Main Street, Bar Harbor, Maine 04609 USA

Please note that this strain has been cryopreserved by the Jackson Laboratories, but the Jain Foundation maintains a private colony of these mice for public use. To obtain these mice, please contact the Jain Foundation:

Jain Foundation Inc.
9706 Fourth Ave NE, Suite 101
Seattle, Washington 98115
Phone: 425-882-1492
Fax: 425-882-1050

Email: admin@jain-foundation.org

Development:
In these mice the progressive muscular dystrophy (prmd) allele from the A/J inbred strain is crossed onto the C57BL/6 genetic background. The cross was performed in the laboratory of Dr. Isabelle Richard at Genethon and the backcross generation reached N8. In collaboration with the Jain Foundation, Dr. Richard donated the strain to The Jackson Laboratory in 2010. Upon arrival, mice were bred to C57BL/6J for at least 2 generations to establish the colony.

Mutation:
An ETn retrotransposon (5-6kb) is inserted in intron 4 of the dysferlin gene.

Symptoms:
Disease onset is observed by 2 months and is characterized by the presence of centronucleated fibers and areas of inflammation. As seen with the original background A/J, mice homozygous for the prmd allele on the C57BL/6J background display an increasing number of centronucleated fibers and impairment in the majority of muscles by 4 months of age. In order of severity, the most affected muscles are psoas, quadriceps femoris, tibialis anterior, and gastrocnemius. Mice exhibit a decreased membrane repair capacity following laser wounding experiments. In an open space assay, mice cover less distance and are less active than wild-type. Mice that are homozygous for this allele are viable, fertile and normal in size.

Comparison with other disease strains:
Disease progression is similar to A/J: slightly slower than in SJL/J, Dysf-/- (Campbell), Dysf-/- (Brown), and C57BL/10.SJL mice. As in both SJL/J and Dysf-/- (Brown) mice, proximal muscles are more severely affected than distal muscles. As in Dysf-/- (Brown) mice, abdominal muscles are also affected.

Control strain(s):
C57BL/6 (for homozygotes); littermates (for heterozygotes).

References:
Lostal W; Bartoli M; Bourg N; Roudaut C; Bentaib A; Miyake K; Guerchet N; Fougerousse F; McNeil P; Richard I. 2010. Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum Mol Genet 19(10):1897-907.

PMID: 20154340

Human Dysferlin protein - Human dysferlin protein purified by Dr. Bryan Sutton's lab is available. To obtain the human dysferlin protein contact the Jain Foundation at admin@jain-foundation.org.

Human Biospecimens – Plasma, serum, DNA, RNA, fibroblasts, cell lines, and biopsy material from genetically confirmed dysferlinopathy patients

Data Resources – natural history clinical data sets, miRNA, RNA, protein, and cytokine data sets, and mouse proteomic and lipidomic data sets

Study Recruitment – support for recruiting dysferlinopathy patients out of the Dysferlin Registry for surveys, studies, and clinical trials

Pre-proposals

• Pre-proposals are encouraged.
• Researchers are welcome to contact the Jain Foundation with a 1-2 page “pre-proposal” to gauge our level of interest at any time.
• Please send pre-proposals to admin@jain-foundation.org.

Dysferlin Registry 

Clinic Support Program 

Clinical testing and Diagnostic support 

Development of Standards of Care 

Patient and Physician Education - LGMD Masterclasses, Patient Educational Series, Healthcare Professionals FAQ, Automated LGMD Diagnostic assistant (ALDA) 

Dysferlin Conferences and Webinars  – We frequently gather experts from around the world to discuss to discuss the state of the field, come up with solutions to challenges, and identify new directions to pursue  

Jain Foundation Scientific Advisory Board (SAB) – The SAB, an in house team of motivated and focused individuals with strong scientific backgrounds, has deep understanding of dysferlinopathy and are willing and available to answer any questions or discuss any potential research project 

Dysferlin Facts 

Relevant publications 

Research grants – We provide funding for basic, translational, and clinical research from academia and industry that align with our goals 

Research tools – From cell lines to antibodies to animal models and DNA constructs, the Jain Foundation has worked hard to create and gather all the tools necessary to study dysferlinopathy 

Preclinical platform – The Jain Foundation has developed an MRI platform for the evaluation of potential therapeutic intervention in mouse models of dysferlinopathy 

Natural History and Clinical Study Data – The Jain Foundation has funded a natural history of study of over 200 genetically confirmed dysferlinopathy patients.  The data from this study is available to both academia and industry 

Human Biospecimens 

Study Recruitment Support 

Summary: A number of findings have come to our attention at the Jain Foundation highlighting a connection between dysferlin and lipid storage, transport, and metabolism.  These observations include recent publications as well as unpublished results from current research projects, involving a wide range of different observations.  We feel these data, taken together, are telling us something important about dysferlin’s role in muscle health—but we aren’t sure what that is.  For this reason, we think it’s important for the research community to see and discuss the recent results on dysferlin and lipids and generate hypotheses and ideas for future studies.  We had planned a session devoted to this topic in the Dysferlin Conference that was scheduled to take place in March 2020.  Due to the in-person conference’s postponement caused by the COVID pandemic, we decided to hold a webinar over two days, featuring findings from several labs on the dysferlin/lipid connection, with time for the community to discuss the observations and their implications.

Summary: Cells typically maintain very low levels of intracellular calcium, as it is used for a variety of signaling and proteolytic functions.  For muscle fibers, however, a large calcium release from the endoplasmic reticulum initiates contraction, necessitating specialized calcium-handling adaptations in muscle.  There is increasing evidence that dysferlin is part of muscle fibers’ calcium management system, as studies from different laboratories have shown that muscle’s calcium handling is altered in dysferlin’s absence.  Dysferlin is known to bind calcium via its C2 domains and changes its behavior in terms of binding to lipids, to itself, and to other proteins at elevated calcium concentration.   This was noted in the context of dysferlin’s role in membrane repair, where an increased calcium concentration occurs due to diffusion from the cell’s exterior.  Dysferlin’s role in regulating calcium, however, appears to be broader, and extend to managing intracellular calcium during contraction. This webinar presents recent work from several research groups which offers clues to dysferlin’s role in managing calcium, and the effect on muscle fibers’ calcium handling when dysferlin in absent.

The Jain Foundation Scientific Advisory Board is unique in that it consists of an entirely in-house team of motivated and focused individuals with strong scientific backgrounds. There is no external advisory board. All proposal reviews and funding decisions are carried out exclusively by the in-house team.

The members of the Jain Foundation team have PhDs in biology-related fields and significant laboratory experience. In order to join the Foundation, they have abandoned the traditional path of an experimental biologist and no longer have any conflicting interests in academic science. For brief biographies of the team members, please visit our team. The Jain Foundation team's role includes and surpasses that of a typical Scientific Advisory Board: they identify the most pressing scientific questions in the dysferlin field, often design specific experiments to address these questions, identify and solicit proposals from laboratories with the expertise to perform the necessary experiments, and monitor the progress of the projects.

Having a team dedicated to one cause has enabled the Jain Foundation to become a center of excellence, capable of a comprehensive and real time assessment of the state of the field with the means to foster collaborations between previously isolated researchers.

The Wellstone Muscular Dystrophy Specialized Research Center at the University of Iowa has a repository of a broad spectrum of skeletal muscle biopsies from neuromuscular diseases patients including those with dysferlinopathy.  Click here to obtain information on how to request these samples. 

Skin fibroblasts were obtained from a skin biopsy from 71 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS).  These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom.  Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application.   Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources).  For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.   

RNA was obtained from 160 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS).  These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom.  Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application.   Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources).  For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.   

Genomic DNA was obtained from 160 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS). These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom.  Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application.   Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources).  For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.   

Yearly plasma and serum aliquots were obtained from 150 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS).  These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom.  Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application.   Correlation with clinical measures from the same time period is also available (see information in Data Resources.  For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.

Proteomic and lipidomics data sets are available from the evaluation of the quadricep muscles of 18wk old mice wild-type versus dysferlin deficient Bla/J mice.  This data was developed by Dr. Frances Lemckert.  To request access to this data contact Dr. Lemckert at frances.lemckert@sydney.edu.au. 

Data sets are available from the evaluation of dysferlinopathy patient samples for possible miRNA, mRNA, protein, and cytokine blood based biomarkers.  This data was obtained through a collaboration between the Jain Foundation and PROOF Centre of Excellence based in Vancouver, BC Canada. To request access to this data please contact the Jain Foundation at admin@jain-foundation.org. 

200+ genetically confirmed dysferlinopathy patients were recruited for the International Clinical Outcome Study of Dysferlinopathy (i.e. COS), which evaluated them over 3-5 years.  A combination of medical, physiotherapy, laboratory, MRI, patient questionnaires and patient reported outcome measures (PROMS) were performed on each participant according to their level of ability.  Requests for this data should be directed to Heather Hilsden at heather.hilsden@newcastle.ac.uk.  Click here for links to publications on the COS data.   For help determining the most appropriate data to request for your research needs contact the Jain Foundation at admin@jain-foundation.org. 

Laurie Long
Office Management and Study Coordination

Ms. Long brings a depth of knowledge and a comprehensive skill set stemming from over 20 years’ experience in administrative and operations support positions. She plays a critical role in maintaining accuracy, preparedness and reputation that have been established by the Jain Foundation in the field of Dysferlin research. Ms. Long coordinates logistical operations at the office as well as finance, project management and study coordinating. Her passion for technology is utilized in day to day tech support as well as with the patient registry software. 

Ms. Long joined the Jain Foundation team in 2017.

Joshua Thayer, Esq.
General Counsel

Mr. Thayer earned his J.D. from Boston College Law School and his A.B. from Harvard University, where he studied the Soviet political system and Russian language, literature and history.  As General Counsel of the Jain Foundation, Mr. Thayer is responsible for providing his scientific and management colleagues with effective advice on company strategies and their implementation, and for drafting and negotiating a variety of operational agreements, including license agreements, clinical trial agreements, research funding agreements, and service agreements.

Prior to joining the Jain Foundation, Mr. Thayer was a partner in the Business Law Department of Edwards Wildman Palmer, which has become a part of Locke Lord since his departure.  Mr. Thayer has over 22 years of experience as a corporate transactional lawyer advising clients within the life sciences industry at all stages of their development.  He has a broad background in general corporate representation, venture capital financing, mergers and acquisitions, public offerings and securities law compliance, with a particular focus on licensing transactions among biotechnology and pharmaceutical companies.  Mr. Thayer has also worked extensively with the technology transfer offices of universities, hospitals and other research institutions.

Bradley Williams, PhD
Director of Research & Diagnostic Innovation

Dr. Williams earned his Ph.D. in Applied Physics from Cornell University and previously worked as a physicist at the Naval Research Laboratory in Washington, DC. He is also a self-taught expert on dysferlinopathy and has a long history of involvement in the dysferlin field. He created the first website about dysferlin deficiency in 2001.

Dr. Williams has been an advisor to the Jain Foundation since its inception in 2005 and joined the foundation full time in 2015. His extensive knowledge of the key players and findings in the dysferlin field has been an invaluable resource for foundation. Dr. Williams serves as a member of the Jain Foundation Scientific Advisory Board and provides advice primarily on projects related to medical physics, promising therapeutic drug candidates, patient diagnosis, and dysferlinopathy disease progression / natural history.  He also assists with interactions, education, and recruitment of individuals with dysferlinopathy through various social media platforms.

Akshay Jain
Chairman and CEO

Akshay Jain cofounded the Jain Foundation with his father Ajit in 2005 after being diagnosed with dysferlinopathy in 2001.  He attended NYU with a focus on finance.  In addition to being the CEO and Chairman of the Board, Akshay manages the endowments of the Foundation.

Sarah Shira Emmons, MPH
Vice President of Patient Affairs and Community Strategies.

Sarah Shira Emmons earned a Master of Public Health degree from the University of Washington, School of Public Health, with a focus on Health Systems, and Population Health. Her research involved exploring behavior change theory through clinical and community-based programs serving oppressed communities and conducting qualitative research, investigating the clinical experiences of individuals with dysferlinopathy.

Ms. Shira Emmons leads and implements the Jain Foundation's patient identification and engagement efforts globally.  She interacts extensively across sectors to expedite diagnostic support, inter-collaborator connection and to align all community members for successful clinical trials for dysferlinopathy. She develops and manages the foundation’s Dysferlin Registry, guides clinical research projects, designs engagement strategies, and conceptualizes initiatives to amplify the impact of the foundation.

Laura Rufibach, PhD
Co-President

Dr. Rufibach earned her Ph.D. in Molecular and Human Genetics from Baylor College of Medicine, where she studied genotype/phenotype correlations and identified new disease genes for a form of peripheral neuropathy. Her postdoctoral research at the University of Washington centered on the identification of structure/function relationships in dystrophin and how that information could be used to construct mini-dystrophin vectors for use in gene therapy in Duchenne muscular dystrophy. 

Dr. Rufibach is a senior member of the Jain Foundation Scientific Advisory Board, which is responsible for implementing the strategic goals of the foundation, identifying the most pressing scientific questions in the dysferlin field, designing experiments to address these questions, identifying and soliciting proposals from laboratories with the expertise to perform these experiments, actively monitoring the progress of funded projects, and fostering collaborations between previously isolated researchers. In addition to her role on the advisory board, Dr. Rufibach oversees the foundation’s patient and physician outreach efforts, implements the foundation’s legal requirements, and leads the foundation's clinical efforts, including directing the upcoming clinical outcome study of dysferlinopathy and determining the best therapeutic candidates for clinical trials.

Doug Albrecht, PhD
Co-President

Dr. Albrecht earned his Ph.D. from the University of California, Los Angeles, where he studied muscle adaptation and remodeling. His postdoctoral research focused on the signaling aspects of the dystrophin cytoskeletal scaffold at the University of North Carolina at Chapel Hill and the University of Washington. 

Dr. Albrecht is a senior member of the Jain Foundation Scientific Advisory Board, which is responsible for implementing the strategic goals of the foundation, identifying the most pressing scientific questions in the dysferlin field, designing experiments to address these questions, identifying and soliciting proposals from laboratories with the expertise to perform these experiments, actively monitoring the progress of funded projects, and fostering collaborations between previously isolated researchers. In addition to his role on the advisory board, Dr. Albrecht is also leading the foundation‘s assay development and preclinical analysis efforts, which are being conducted in partnership with contract research organizations.

Below is a quick summary of the inclusion/exclusion criteria.  Please review this information carefully prior to making any decision regarding participating.

Inclusion Criteria:

• Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
• Established mutations of the dysferlin gene on both alleles
• Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
• Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).

Exclusion Criteria:

• Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
• The presence of dysferlin mutations without weakness or loss of function
• Symptoms or signs of cardiomyopathy, including:
• Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
• Echocardiogram with ejection fraction below 40%
• Diagnosis of (or ongoing treatment for) an autoimmune disease
• Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
• Pregnancy
• AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay
• Abnormal laboratory values in the clinically significant range in the table below, based upon normal values in the Nationwide Children's Hospital Laboratory: GGT, Total Bilirubin, Cystatine, Hemoglobin, White Blood Cells
• This first phase of the trial will be small and will only evaluate safety; patients enrolled are not expected to show improvement in their symptoms.  If the initial trial is successful, a Phase 2 trial will be scheduled, which will look for efficacy (improvement in symptoms) as well as safety. Each phase would include more patients. So, it is a process and we are pacing ourselves as we support this major milestone in the field of therapeutic intervention for people suffering from dysferlinopathy.