It’s time for research updates! BDSRA Foundation’s Head of Research & Medical Affairs Dr. Ineka Whiteman breaks down Batten disease clinical program updates, research news & opportunities, and resources in her monthly column, as seen in BDSRA’s monthly newsletter, The Illuminator. (Note: this Post-April edition was published after the April edition of The Illuminator and therefore was not inlcuded in the newsletter).
As I reflect on recent months (and sit down long enough to catch my breath and write this column), I am excited to share a recap of just some of the impactful research and medical affairs endeavors that have been keeping me and our small but mighty team very busy of late. It’s been an honor to witness the dedication and passion our team pours into each project, furthering our mission to support Batten families, fund and facilitate research, and advocate for treatments and a cure.
KEY MILESTONE ACHIEVED IN THE CENTERS OF EXCELLENCE PROGRAM
Since November last year, the Center of Excellence Working Party comprised of more than 15 expert clinicians from around the U.S. has continued to meet every month via Zoom to collaboratively develop and implement the forthcoming national CoE Program. As Program Lead, I have been immensely encouraged and energized by the dedication and genuinely collaborative spirit shown by this team as we’ve worked tirelessly together behind the scenes to develop the Program foundations and Standards for Designation.
In April, we were excited to finalize the inaugural Center of Excellence program model and the founding network of nine Centers across the U.S. Together, this network aims to:
- Enhance access to the highest level of comprehensive Batten-specific care for patients and their families;
- Advance clinical research and drive patient access to emerging therapeutics;
- Provide Batten-specific professional support and education to other healthcare providers, and…
- Collaborate with the BDSRA Foundation in its mission to continually improve the lives of those affected by Batten disease, and to drive research towards treatments and cures.
BDSRA will formally announce and introduce the nine new Centers at the Annual Family Conference Dinner in St. Louis on Saturday, July 13. Center Directors and representatives will join us in person on the night and throughout the weekend to participate in conference program sessions – this is an event not to be missed!
DRIVING MAJOR RESEARCH COLLABORATIONS
Put simply, collaboration fuels innovation. In recent months, we’ve forged several new strategic research partnerships and initiatives with leading healthcare institutions, research organizations, patient advocacy groups, and industry stakeholders – both in the U.S. and worldwide. Two of these are described below, and we look forward to sharing more news as these, along with our other projects, continue to evolve.
CLN1 Natural History Study Global Roundtable
As many in our community are aware, there has been a lot of encouraging activity in the CLN1 clinical research landscape in recent months. Through our ongoing engagements with colleagues around the world, BDSRA has identified numerous stakeholders currently invested in the development of treatments for CLN1 disease and/or natural history studies that are equally vital to therapeutic development. With an active global CLN1 family network positioned and ready to help drive these initiatives forward, it’s an opportune time to bring the key stakeholders together to discuss and take action on potential opportunities for research collaborations. Later in May, BDSRA will host a virtual roundtable meeting to facilitate these discussions, and we look forward to reporting back next month.
Batten Disease Research Grants – Watch this space!
We have been busy assembling a very special group of people who have begun laying the foundations for a brand-new research grant initiative launching this July. The initiative aims to drive and foster the most promising, innovative, and meaningful world-class research across a breadth of areas from the more traditional basic, translational, and clinical-based research to more quality-of-life and supportive care-focused research. We cannot wait to unveil this exciting new initiative during the Annual Family Conference in July.
FAMILY CONFERENCE UPDATE
And speaking of the Annual Family Conference, our educational program is shaping up to be one of our best and most interactive yet. Sessions will feature in-person presentations from local and international researchers, interactive Ask-A-Doc sessions with Centers of Excellence directors and senior clinicians, the latest clinical trial and pipeline updates, including Q&A with our industry partners, and the interactive “NCL Researchers Challenge” where researchers are invited to present their latest findings via 3-minute video presentations, with attendees voting for their favorites through the Conference app.
So here’s to another month of making strides together, pushing boundaries, and advocating tirelessly for our Batten children and their families. I want to personally thank YOU, our community, for your incredible support and dedication to our shared mission.
Warm regards,
CLINICAL PROGRAM UPDATES
Clinical Trial Tracker
Keep up-to-date with the latest clinical trial and natural history study news with our Clinical Studies Chart on the BDSRA Foundation’s website. Check it out by clicking here.
Latus Bio Launches with State-of-the-Art Gene Therapy for CLN2 disease
On May 2, the biotechnology company Latus Bio, Inc. (“Latus”), announced its launch with an initial $54 million in Series A financing and two lead product candidates currently in pre-clinical development for the treatment of CLN2 disease and Huntington disease, respectively.
Latus co-founder, Professor Beverly Davidson at the Children’s Hospital of Philadelphia (CHOP), is a researcher well-known to the Batten disease scientific community. Using proprietary technologies to identify and engineer novel adeno-associated virus (AAV) capsid variants, Prof. Davidson and her team are developing CNS (brain and spinal cord)-directed gene therapy candidates to show unprecedented potency, specificity, and safety profiles.
Read more by clicking here.
Theranexus and BBDF announce final and positive safety and efficacy data in Phase I/II Batten-1 trial, and updates on Phase III study
In a letter to its CLN3 family community on April 20, the Beyond Batten Disease Foundation shared the latest press release reporting positive efficacy results after 18 months for patients in the Phase I/II Batten-1 clinical study.
As previously reported in mid-February, BBDF stated, “The Phase III trial for Batten-1 is experiencing some unanticipated delays but continues to be our highest priority. Theranexus recently had a funding partner withdraw unexpectedly due to an internal strategic issue unrelated to the Batten-1 program. While pursuing some additional sources and talking with a number of parties who can provide the capital necessary to fund the trial, BBDF and Theranexus are exploring several promising alternatives.
This delay is providing an opportunity for us to review the FDA’s feedback and discuss and consider alternative regulatory strategies to bring the drug to patients within the shortest time frame.”
Click here to read a summary of the Batten-1 data, and for further information, please reach out to Mary Beth Kiser, President and CEO at BBDF at mbkiser@beyondbatten.org.
RESEARCH CONFERENCE NEWS
Save the Date: Translational Research Conference for the Management of NCLs
Held on alternate years to the International Congress on Neuronal Ceroid Lipofuscinosis (NCL Congress) this bi-annual meeting is for families, researchers, and industry experts to discuss gaps, lessons learned, and emerging therapeutic approaches in NCL preclinical and clinical research.
The 8th Translational Research Conference will be held in Chicago, at the Westin Chicago Lombard on November 20-22, 2024. There will be more details to follow.
To join the mailing list for updates on this conference, please email ResearchEvents@sanfordhealth.org.
FAMILY REGISTER
Have you joined the Register yet?
The BDSRA Foundation Family Register is a vital tool that enables us to keep you informed of ongoing Batten disease research, including future clinical research and natural history opportunities.
The Register also enables BDSRA to understand more the prevalence of Batten disease, including the different subtypes and geographical locations. This helps us tailor our education and support activities according to the needs of our families. The Register is open to all current and bereaved families in the U.S. and internationally.
The information collected in this form is kept STRICTLY CONFIDENTIAL. Your involvement in this survey is entirely voluntary, and you may request to be removed from the list at any time. The form takes just a few minutes to complete and can be accessed by clicking here.
Thank you for participating in this important initiative!
RESEARCH OPPORTUNITIES
Characterizing Sleep in Batten Disease
Principal Investigator: Heather Adams, Ph.D.
Research sponsor: Batten Disease Support, Research, & Advocacy Foundation
The University of Rochester Batten Center is conducting a study of sleep function in individuals with CLN2 and CLN3 Batten disease.
What is involved?
Affected individuals will provide saliva samples to test melatonin concentration, and wear an actigraph (a wrist-watch style activity monitor). Parents/caregivers will assist the affected individual with study activities and will complete questionnaires.
Who may be eligible?
Affected individuals who…
- have a confirmed genetic or enzyme-based diagnosis of CLN2 or CLN3 disease
- have any symptoms of CLN2 or CLN3 disease
- are at least 2 years old
- live at home with at least one primary caregiver
- have not taken oral melatonin in the past 2 weeks (before study participation begins), or have only taken it occasionally (no more than 3 times per week)
No travel is required! All study activities will take place at your own home. This study is open to families currently residing in the U.S.
The affected child & parent will receive $200 (total for household) for participation in the research.
If you are interested in learning more about the study, please contact the study team at Batten@URMC.Rochester.edu or call Study Coordinator, Marianna Pereira-Freitas at: (585) 274-0205.
PUBLICATION HIGHLIGHTS – April 2024
Peripheral retinal finding on fluorescein angiography in neuronal ceroid lipofuscinosis type 2 (CLN2)
Rogers DL, et al. J AAPOS. 2024 Apr;28(2):103830
ABSTRACT
Classically, peripheral vascular changes in the retina in patients with neuronal ceroid lipofuscinosis type 2 (CLN2) are described as vascular attenuation seen in the late stages of disease on the Weill Connell Ophthalmic Severity Score (WCOSS) staging system. We describe isolated, mild, peripheral vasculitis with peripheral arteriolar dropout identified by fluorescein angiography in patients with a WCOSS grade of stage 2. We believe this vasculitis represents an early vasodegenerative phase of disease that leads to the vascular attenuation seen in later stages of the disease.
Access the article by clicking here.
A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis
Madhana KP, et al. Metab Brain Dis. 2024 Apr;39(4):545-558
ABSTRACT
Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and – 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder.
Access the article by clicking here.
Progressive Visual Loss Is Not Always Accompanied by Neurodegenerative Disorder in Juvenile Neuronal Ceroid Lipofuscinosis: A Case Report
Hundsberger F, et al. Klin Monbl Augenheilkd. 2024 Apr;241(4):538-539.
ABSTRACT
Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the many types of NCLs, which are a group of inherited neurodegenerative lysosomal storage disorders. Type 3, the classic and most common form, is caused by homozygous or compound heterozygous pathogenic variants in the CLN3 gene that encodes a lysosomal transmembrane protein. This yields in unbalanced cellular homeostasis and increased neuronal loss, as the physiological protein is predicted to be a pH regulator and modulator of vesicular transport and fusion [1]. Clinical symptoms mostly present between 5 – 10 years of age and manifest as progressive vision loss and, rarely, seizures. Cognitive and behavioural impairment is thought to appear a few years after the onset of visual impairment [1]. This is, however, not always the case. The aim of this case report is to describe the unusual phenotypic presentation of juvenile NCL3 in a patient of Swiss descent.
Click here to access the article.
Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia
Saleh MM, et al; Pediatr Neurol. 2024 Mar 7;155:149-155.
ABSTRACT
Background: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population.
Methods: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed.
Results: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14.
Conclusions: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.
Click here to access the article.
