On August 2, 2018, ArmaGen, Inc., a biopharmaceutical company located in Calabasas, California, announced that the U.S. Food and Drug Administration’s Office of Orphan Products Development has granted Orphan Drug Designation to its investigational agent AGT-184 for the treatment of lysosomal disease mucopolysaccharidosis type IIIA (also known as MPS IIIA, or Sanfilippo syndrome type A). AGT-184 is an investigational enzyme replacement therapy for the treatment of the cognitive effects of MPS IIIA. The missing or diminished enzyme needing therapeutic replacement is N-sulfoglucosamine sulfohydrolase (“SGSH”).
AGT-184 is an immunoglobulin G (“IgG”)-SGSH fusion-protein, where the IgG portion is a human anti-insulin receptor monoclonal antibody. The insulin receptor antibody domain triggers transport of the AGT-184 fusion-protein across the blood brain barrier, by binding to endogenous insulin receptors present on the blood brain barrier. Normally, the blood brain barrier blocks large molecules such as enzymes from entering the brain. In effect, this is a Trojan Horse approach to successfully delivering the therapeutic agent to the brain. ArmaGen, Inc. is currently conducting Investigational New Drug (“IND”) application-enabling activities (manufacturing, toxicology studies), with the goal of filing an IND application with the U.S. Food and Drug Administration in late 2019.
The FDA grants Orphan Drug Designation to drugs intended to treat a rare disease or condition affecting fewer than 200,000 people in the U.S. This designation confers special financial incentives to the drug developer, including tax credits on clinical development costs and prescription drug user-fee waivers, and it may confer the right to seven years of market exclusivity in the U.S. upon FDA approval of the orphan drug.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is one of the new technologies some researchers are using to explore possible genetic treatment of rare genetic disease. CRISPR is a tool for precision gene editing.
This episode of NOVA, which originally was broadcast by PBS in the United States on May 23, 2018, describes how some researchers are using CRISPR. You may wish to skip to minute 32 to see how gene therapy may help the adrenoleukodystrophy (“ALD”) community.
For an even shorter overview of how CRISPR works, check out this 1.5-minute NOVA Wonders video By Michael Rivera.
CRISPR is one of the topics that will be addressed by expert speakers at “The Next Revolution: Genome Engineering 2018” conference at the University of Minnesota in Minneapolis, July 19-21, 2018. For more details visit our Calendar page, where events are shown in chronological order.
The Lysosomal Disease Network (LDN) issued a Request for Proposals (RFP) for studies aiming to participate in the competitive re-application to the National Institutes of Health “Rare Diseases Clinical Research Network” program. Details are provided in this document.
A Letter of Intent (LOI), with outline (a brief outline addressing proposed elements of the standard NIH PHS 398 form), was due at the LDN office on January 1, 2018. Following a brief constructive response from the LDN to their LOI and brief outline, completed outlines of applications were due by January 30, 2018. On February 9, 2018, a “Pitch Meeting” occurred at the LDN Expert Advisory Committee gathering at the Manchester Grand Hyatt San Diego Hotel, San Diego, California, USA. At that time each applicant delivered an oral presentation of their proposal to the LDN Expert Advisory Committee.
The Lysosomal Disease Network (LDN) is pleased to announce that it has selected Laura Adang, MD, PhD of The Children’s Hospital of Philadelphia for a fellowship that provides $50,000 for lysosomal disease clinical research. Her research project is entitled “Metachromatic leukodystrophy: characterization of genetic mutations, age of onset, and clinical subtypes.” Dr. Adang’s mentor for this project is Dr. Adeline Vanderver, also with The Children’s Hospital of Philadelphia. Dr. Adang’s fellowship period is August 1, 2017 – July 31, 2018. Click here for more information about the LDN’s fellowship opportunities.
The project is a multi-center retrospective natural history study to characterize the disease course in patients affected by metachromatic leukodystrophy (MLD). It will use statistical modeling to analyze collected clinical data to classify distinct subpopulations within the heterogeneous MLD population. Ultimately, it will evaluate the correlation and distinctions between the subpopulations with respect to genetic, radiographic, and ancillary clinical phenotypes, including gallbladder and renal involvement. Dr. Adang said the project goals include “validating or possibly redefining the clinical subtypes of metachromatic leukodystrophy. This can be used to design future studies and therapeutic trials. Importantly, with a better understanding of metachromatic leukodystrophy, we will be able to offer our families better anticipatory guidance, establish appropriate standards of care, and design better future therapeutic trials.”
Dr. Marc Patterson, Director, Education Core of the Lysosomal Disease Network, said “The Lysosomal Disease Network looks forward to a very productive research project, and wishes Dr. Adang the greatest success in achieving the goals of this research project, with a peer-reviewed publication summarizing the findings. Dr. Adang will also participate in the NIH-funded RDCRN Rare Disease Clinical Research Training Program, which is also open to new clinical investigators.”
You (or your child) are invited to participate in the nationwide Contact Registry for lysosomal disease patients. The Rare Diseases Clinical Research Network (RDCRN) offers this patient Contact Registry. This is a method by which patients with lysosomal diseases can register themselves online with the RDCRN in order to be contacted in the future about clinical research opportunities and updates on the progress of the research projects. The contact registry is anonymous and free of charge.
The Lysosomal Disease Network encourages lysosomal disease patients or their families to register. Because of the rarity of lysosomal diseases, the Contact Registry plays an important role in estimating the incidence and prevalence of these conditions, and in keeping interested persons informed about available clinical research for treatment and cure of lysosomal
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is sponsoring an ongoing research study entitled “Clinical Biomarkers in Alpha-Mannosidosis” at the NIH in Bethesda, Maryland. This study is seeking participants between 5 and 60 years of age who have been diagnosed with alpha-mannosidosis. Most especially, the study is seeking participants under 10 years old to study the early progress of the disease. Bone marrow transplantation does not disqualify persons from participation. Minors will need permission from their parents.
There is no treatment or cure for this rare lysosomal disease at present. The primary outcome measure of this research study is identification of cerebrospinal fluid biomarkers that could serve as candidate surrogate markers of treatment effect in a future clinical trial. Such information is required and is essential for conducting any future clinical trials of treatments for alpha-mannosidosis. The investigators have written that “if the pre-clinical components of this proposal prove promising, the prospect of a recombinant adeno-associated viral gene therapy trial involving a brain-directed (intrathecal) approach for alpha-mannosidosis would be possible within 3 years.”
Participants will have three outpatient study visits, about once a year for 2-3 days each time, at the NIH campus in Bethesda, Maryland. Participants will have a medical history obtained, a physical examination, laboratory tests, and samples collected. Travel and lodging are covered and there are no costs for participation or tests. ClinicalTrials.gov provides extensive details, and questions can also be directed to Kristen Stevens at the NIH. Spread the word — and THANKS!
The NCL Foundation, a German research-oriented patient advocacy group, aims to help find a cure for neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease, which is a large lysosomal disease-group affecting humanity worldwide. This research Award of €50,000 is intended to support a postdoctoral fellowship for one year. The Foundation highly encourages junior scientists and clinical researchers worldwide to submit projects that hold promise to help halt, or find a cure for, Batten disease. They also encourage scientists to apply for this Award who work in disease areas outside NCL, but which are relevant to cell and molecular pathways of CLN3 dysfunction.
The deadline for submitting all required documents is October 31, 2016. For extremely detailed information and the downloadable application form (which must be used), please visit: NCL Research Award: Call for Proposals.
The U.S. Food and Drug Administration (FDA) is making $2 million available in new research grants to fund natural history studies in rare diseases. The aim is to collect data on how specific rare diseases progress in individuals over time. This knowledge can inform and support drug product development and approval. This will be the first time the FDA will provide funding through its “Orphan Products Grants” to conduct natural history studies for rare diseases.
Natural history is the course a disease takes in affected individuals from the time immediately prior to its inception, progressing through a pre-symptomatic phase and different clinical stages, to a final outcome in the absence of treatment. This type of information is often not available, or incomplete, for many rare diseases, and this makes the drug-approval process additionally difficult.
The funding levels and duration of these grants will include:
● A maximum of $400,000 in total costs per year for up to five years for prospective (looking forward) natural history studies involving clinical examination of affected individuals.
● A maximum of $150,000 in total costs per year for up to two years for retrospective (looking back) natural history studies (i.e., chart review) or survey studies (i.e., questionnaire).
Grant applications are due not later than Oct. 14, 2016. All responsive applications will be reviewed and evaluated for scientific and technical merit by a panel of rare disease and natural-history experts. The anticipated start date of funding for grantees is March 2017.
Lysosomal diseases are a collection of more than 70 clinical syndromes with incidence rates ranging from 1 in 20,000 live births (Gaucher disease) to 1 in 300,000 live births (Wolman disease). Taken together, lysosomal diseases are responsible for a significant amount of disability and disease burden.
Testing New Therapies
The rarity of each lysosomal disease means that no single medical research center has an opportunity to see sufficient numbers of patients with any one lysosomal disease to effectively describe its full spectrum, or to adequately test any new therapies.
Combined and Integrated Efforts
The combined and integrated efforts of the Lysosomal Disease Network (“LDN”) focus on creating a network of centers with expertise in one or more of these diseases in order to solve major challenges in diagnosis, disease management, and therapy. Solutions to these problems will have a direct impact on patients suffering from lysosomal disease and important wider implications for medical practice.
aspartylglucosaminuria; Batten disease (neuronal ceroid lipofuscinosis (NCL) (infantile, late infantile, juvenile, and adult-onset)); cystinosis; Danon disease; Fabry disease; Farber’s lipogranulomatosis; fucosidosis; galactosialidosis types I, II and III; Gaucher disease types I, II and III; glycogen storage disease; GM1 and GM2 gangliosidoses (infantile, juvenile, and adult-onset); Krabbe disease; lysosomal acid lipase deficiency (LALD) including Wolman disease and cholesterol ester storage disease; alpha-mannosidosis types I and II; beta-mannosidosis; metachromatic leukodystrophy; mucolipidosis types II, III, and IV; mucopolysaccharidosis (MPS) types I, II, III, IV, VI and VII (Hurler, Hurler–Scheie, and Scheie; Hunter, Sanfilippo, Morquio, Maroteaux–Lamy, and Sly syndromes, respectively); multiple sulfatase deficiency; Niemann–Pick disease types A, B and C; Pompe disease; Sandhoff disease (infantile and juvenile-onset); Schindler disease types I and II; sialidosis types I and II; Tay-Sachs disease (infantile, juvenile and adult-onset).