CLN7 disease is a rare, fatal and rapidly progressive neurodegenerative disease that is a form of Batten disease. CLN7 is caused by autosomal recessive mutations in the MFSD8 gene that results in lysosomal dysfunction. Disease onset occurs around two to five years of age, with death often ensuing in young adolescence. Patients experience gradual nerve cell loss in certain parts of the brain and typically present with seizures, vision loss, speech impairment and mental and motor regression. Currently, there are no approved therapies to treat CLN7 disease, which impacts an estimated 4,000 patients globally.
Preclinical data in rodents supported advancement of the first-generation construct into a Phase 1 clinical proof-of-concept study in patients with CLN7 disease. In an in vivo efficacy study, intrathecal (IT) administration of the first-generation construct to MFSD8 knockout mice with high or low doses resulted in clear age and dose effects with early intervention and high dose achieving the best therapeutic benefits. IT high dose of the first-generation construct in younger knockout mice resulted in: 1) widespread MFSD8 mRNA expression in all tissues assessed; 2) nearly complete normalization of impaired open field and rotarod performance at 6 and 9 months post injection; 3) more than doubled median life expectancy (16.82 months versus 7.77 months in untreated knockout mice); and 4) maintained healthy body weight for a prolonged period of time. Toxicology studies in wild type rodents demonstrated safety and tolerability of IT administration of the first-generation construct. These preclinical data will be presented by Xin Chen, Ph.D., Assistant Professor, Department of Pediatrics at UT Southwestern, in an oral presentation at the 17th Annual International Congress on Neuronal Ceroid Lipofuscinosis on October 8, 2021.
“The CLN7 program is a strategic addition to our gene therapy pipeline focused on monogenic CNS diseases. Encouraging preclinical data generated in relevant rodent models suggest that the first-generation construct has the potential to reduce overall disease pathology, preserve motor function and ultimately prolong survival,” said RA Session II, President, Founder and Chief Executive Officer of Taysha. “The first-generation construct is currently in a Phase 1 clinical proof-of-concept trial with two patients dosed to date, and we look forward to the availability of preliminary data by year-end. With human proof-of-concept clinical data to reference, we expect to advance a next-generation construct into a planned pivotal trial in 2022, which we anticipate should improve potency, safety, packaging efficiency and manufacturability over the first-generation construct. Importantly, we are also pleased to announce our grant to Batten Hope, the leading CLN7 disease non-profit patient advocacy organization, to support patient awareness, disease education and newborn screening initiatives. We believe a gene therapy approach has the potential to address a significant unmet need in an estimated 4,000 patients globally.”
Gina Hann, Batten Hope Founder, President and Treasurer, added, “Our mission is to support families with children suffering from terminal and rapidly progressive neurodegenerative diseases like CLN7. We are honored to receive Taysha’s support to raise awareness, increase newborn screening and help patients gain access to potentially transformative treatments that offer hope and therapeutic advancement for conditions with significant unmet needs.”
UTSW is currently enrolling patients in an investigator-sponsored Phase 1 open-label, dose escalation clinical proof-of-concept trial at Dallas Children’s Hospital for an intrathecally dosed AAV9-based gene replacement therapy for the treatment of infantile CLN7 disease. The primary endpoint of the trial is safety and tolerability by incidence and severity of treatment related serious adverse events. Secondary efficacy endpoints include the Clinical Global Impression, neuropsychological, ataxia and motor function assessments and quality of life. The design rationale and a discussion of outcome measures for this clinical trial will be presented as a poster at the upcoming 17th Annual International Congress on Neuronal Ceroid Lipofuscinosis. To date, one patient has been dosed at 5x1014 total vg and a second patient was dosed at 1x1015 total vg as measured by the qPCR method. UTSW continues to enroll patients in this Phase 1 study at 1x1015 total vg and expects to dose additional patients in the near term. Preliminary safety and efficacy data are expected by the end of 2021.
With the addition of the CLN7 program, Taysha expects to have five clinical stage programs by year-end. As such, the TSHA-104 program for the treatment of SURF1-associated Leigh syndrome will transition to the company’s collaborators at UTSW to complete IND-enabling studies, followed by a planned investigator-initiated clinical trial by the end of 2022. Taysha will continue to support the SURF1 natural history study in partnership with UTSW.
Financial terms of the agreements were not disclosed.
Webcast Information
Taysha management will host a webcast today at 8:00 am ET / 7:00 am CT to discuss today’s news. To participate, please access the following link: http://lifesci.rampard.com/WebcastingAppv5/Events/eventsDispatcher.jsp?Y2lk=MTQ1MQ==. The live webcast and replay may also be accessed by visiting Taysha’s website at https://ir.tayshagtx.com/news-events/events-presentations. An archived version of the webcast will be available on the website for 60 days.
