KIF1A

Researchers at the non-profit n-Lorem discovered and developed a personalised ASO therapy to treat a rare neurological disease. Credit: SurfsUp via Shutterstock. A patient with a rare progressive neurodegenerative disorder receiving a personalised experimental antisense oligonucleotide (ASO) treatment developed by the non-profit n-Lorem has reported improvements in seizure severity and quality of life. The patient, named Susannah, has a rare condition called KIF1A-associated neurological disorder (KAND). US-based non-profit n-Lorem developed a personalised, experimental ASO medicine specific to Susannah’s genetic mutation. After receiving her first dose of the personalised medicine, her seizures fell to under 30 per week and she has remained stable. KAND is caused by mutations in the KIF1A gene, leading to progressive motor impairments, developmental delays, and cognitive difficulties. Management of KAND mainly focuses on addressing symptoms and improving quality of life through supportive therapies, like speech or physical therapy. There are no other therapies for KAND in clinical development, as per GlobalData’s Pharma Intelligence Center. GlobalData is the parent company of Pharmaceutical Technology . Following the ASO treatment, the patient’s ability to walk also improved after one month; compared to having an average of 26.2 falls per day before treatment, she now experiences up to seven falls daily, with many days without any falls. See Also: Eli Lilly boosts sales forecast by $3bn as diabetes and weight loss drugs propel revenue Recursion and Exscientia merge to form drug discovery company Data from the study published in Nature Medicine also detail notable advancements in speech, attention, group interaction, and motor functions, while the patient’s cognitive abilities have remained stable. Susannah has continued on the ASO treatment for 20 months, with a favourable safety and tolerability profile. ASO therapies work by using short, synthetic strands of nucleic acids to target and modify specific genes, reducing the production of harmful proteins or correcting genetic defects. The treatment developed by n-Lorem targets and corrects the harmful version of the KIF1A gene. Founded by former Ionis Pharmaceuticals ’ CEO Stanley Crooke, n-Lorem aims to bring ASO therapies to patients who are diagnosed with a disease that is found in less than 30 people. Research physicians submit an application to the non-profit, which examines if the patient’s genetic mutation is amendable to the ASO technology. More than 130 patient applications have so far been approved by the organisation for a range of different mutations. There has been an increase in the number of nonprofits developing rare disease medications where the patient population size is too small for commercialisation. Italian research charity Telethon Foundation manufactures and distributes Strimvelis, a gene therapy for rare disease adenosine deaminase severe combined immunodeficiency (ADA-SCiD). The non-profit took over development after it was dropped by its pharmaceutical company in 2022, allowing patients to receive treatment. ASO therapies have long been investigated in rare diseases because they target the cause of disease at the molecular level. Researchers have also developed candidates that are approved to treat conditions affecting larger patient populations. Biogen ’s ASO Spinraza (nusinersen) secured approval for treating the movement disorder spinal muscular atrophy in 2016, pulling in $610.5m in sales in 2023 as per the company’s financials. In the announcement accompanying the case study, n-Lorem’s CEO Stanley Crooke said: “Prior to treatment, Susannah’s disease had progressed to her being mostly in a wheelchair, approaching nonverbal with debilitating seizures that limited her and her family’s quality of life. Susannah has now been on treatment for more than 20 months and we continue to observe improvements in her mobility, neurological function, and quality of life.” The non-profit, which launched in 2020, is also conducting a KIF1A outcome measures, assessments, longitudinal and endpoints (KOALA) study to understand how KAND symptoms develop and change over time.

SAN DIEGO--( BUSINESS WIRE )-- n-Lorem, a nonprofit foundation , announced today the publication of a case study detailing the treatment and initial outcomes for a nano-rare patient who is receiving treatment with a personalized experimental ASO medicine discovered and developed specifically for that patient. In this report, most outcome measures including seizure severity, number of falls, overall speech and quality of life improved after treatment. The study, authored by the patient’s doctors Wendy K. Chung, M.D., Ph.D., of Boston Children’s Hospital, and Jennifer M. Bain, M.D., Ph.D. of Columbia University Irving Medical Center, along with n-Lorem, was published today in Nature Medicine (Zeigler, A., et al. Nature Medicine advanced online publication, Aug 2024). In this study, the challenges caused by KIF1A-associated neurological disorder (KAND), and the positive impact observed during treatment on Susannah’s neurologic function and quality of life were described. The case study reported that during the 50-day period prior to treatment, Susannah’s parents described 100 and 290 seizures a day. Following her first dose of the personalized experimental ASO medicine developed by n-Lorem, her parents reported the number of seizures dropped to less than 30 a week, where it remained relatively consistent. Similarly, prior to her first dose, Susannah’s ability to walk was severely impaired with an average of 26.2 falls a day. A month after her first dose, her gait improved and the number of falls decreased to a maximum of seven a day, while many days she didn’t fall at all despite being far more active. In addition, researchers noted improvements in her quality of speech, attention level, engagement, ability to interact in group activities and motor function while her cognitive ability remained stable. The patient has now been on ASO treatment for 20 months with a favorable safety and tolerability profile. “ Our goal from the outset with Susannah was to arrest the progression of her disease, which is often fatal. This is the first time a medicine has been able to treat the genetic cause of KAND, halt disease progression and provide meaningful clinical benefit,” said Wendy Chung, M.D., Ph.D., Chair of Pediatrics at Boston Children’s Hospital. “ While Susannah’s medicine was designed to work on her specific genetic sequence, we are hopeful that more KAND patients will potentially benefit from this medicine. Our KOALA study is important in this endeavor, as it allows us to evaluate each patient’s clinical status and genetic sequence to identify which patients may potentially be candidates for this medicine.” “ n-Lorem’s approach is truly personalized medicine, where an individual patient’s genetic profile is used to guide treatment of that patient’s disease. In this case, n-Lorem’s ASO was designed to target Susannah’s specific genetic cause of disease in hopes of halting the progression of her neurodegenerative disease,” said Jennifer M. Bain, M.D., Ph.D. Associate Professor of Neurology and Pediatrics at Columbia University Vagelos College of Physicians and Surgeons. “ Since starting the treatment, Susannah has made improvements far beyond what we expected. We have been able to track how she has advanced from using a wheelchair much of the day to walking, climbing stairs and even playing basketball with her brother. We are hopeful that what we are learning from Susannah can apply to other KAND patients.” KAND is a severe neurodevelopmental and neurodegenerative disorder that is often fatal and can cause irreversible brain and optical nerve atrophy, epilepsy, cognitive impairment and peripheral neuropathy. The disorder is caused by more than 100 mutations in KIF1A , and KAND will require multiple ASOs to treat all KAND patients. In an effort to understand how KAND symptoms develop and change over time, Dr. Wendy Chung’s team is conducting the KOALA study (KIF1A Outcome measures, Assessments, Longitudinal And endpoints study) to advance KAND research by performing longitudinal standardized assessments with KAND patients. “ We are beyond thrilled with the improvements that we have observed in Susannah. Prior to treatment, Susannah’s disease had progressed to her being mostly in a wheelchair, approaching nonverbal with debilitating seizures that limited her and her family’s quality of life. Susannah has now been on treatment for more than 20 months and we continue to observe improvements in her mobility, neurological function and quality of life,” said Stanley T. Crooke, M.D., Ph.D., Founder, Chairman and CEO, n-Lorem Foundation. “ Because the KIF1A protein serves a vital function in the body, our approach required the design of an ASO medicine that would target the copy of the gene that had the mutation, while allowing the other copy of the gene that does not contain the mutation to produce normal KIF1A protein. This selective gene targeting of the ASO allows the functional KIF1A protein to be expressed and available for normal cellular function, while removing the toxic KIF1A protein. There is no other technology that is capable of this gene selectivity, only ASO technology,” continued Dr. Crooke. “ While we hope to see such dramatic improvements in all of our patients, we understand that may not be the case given the broad diversity of target genes, disease progression and disease severity in our patients.” n-Lorem discovered and developed a personalized, experimental ASO medicine specific to Susannah’s needs. The first dose was administered in October 2022 by Drs Chung and Bain at Columbia University Irving Medical Center. Susannah remains on treatment at Columbia Medical Center and continues to see increased clinical benefit from this medication. “ Personalized ASO medicines can be incredibly selective and offer significant therapeutic hope for many nano-rare patients. At n-Lorem, we believe that each patient deserves the very best ASO that we can discover, and we have the expertise, knowledge, automation and experience to do just that for our nano-rare patients,” concluded Dr. Crooke. “ While we are treating one nano-rare patient at a time, what we are learning from a single patient will help entire patient communities and broaden our understanding of how a single gene mutation can cause devastating diseases. We built n-Lorem knowing that one day we might be treating thousands of nano-rare patients.” To learn more about Susannah’s story see n-Lorem website , watch this video created after she started receiving treatment or listen to Susannah’s Journey podcast on the n-Lorem Patient Empowerment Program. About n-Lorem n-Lorem Foundation is a non-profit organization established to apply the efficiency, versatility and specificity of antisense technology to charitably provide experimental antisense oligonucleotide (ASO) medicines to treat nano-rare patients diagnosed with diseases that are the result of a single genetic defect unique to only one or very few individuals. Nano-rare patients describe a very small group of patients (1-30 worldwide) who, because of their small numbers, have few if any treatment options. n-Lorem Foundation was created to provide hope to these nano-rare patients by developing individualized ASO medicines, which are short strands of modified DNA that can specifically target the transcripts of a defective gene to correct the abnormality. The advantage of experimental ASO medicines is that they can be developed rapidly, inexpensively and are highly specific. To date, n-Lorem received over 280 applications for treatment with more than 130 nano-rare patients approved. n-Lorem was founded by Stanley T. Crooke, M.D., Ph.D., former chairman and CEO of Ionis Pharmaceuticals, who founded Ionis Pharmaceuticals in 1989 and, through his vision and leadership, established the company as the leader in RNA-targeted therapeutics. Follow us on Twitter , Facebook , LinkedIn and YouTube . To learn more about n-Lorem’s mission at www.nlorem.org , and please consider giving to n-Lorem to bring hope, possibility and treatment options to these patients and families in need.

Courtesy Bodo Marks/Picture Alliance via Getty Ima Data from pre-clinical studies show that OV350 may be developed to treat multiple types of epilepsy and other CNS conditions, including neurodevelopmental diseases. World is hoping for positive results from this tie-up against epilepsy. (Bodo Marks/picture alliance via Getty Images) Ovid Therapeutics has partnered with AstraZeneca for exclusive access to a library of early-stage small molecules that target the KCC2 transporter, including OV350 — the lead candidate. Under the terms of the deal to find an Epilepsy cure, AstraZeneca will receive $5 million in cash and $7.5 million in shares of Ovid common stock upfront. AstraZeneca also stands to gain up to $8 million in clinical development milestones and up to $45 million in regulatory milestones. OV350 is an early-stage compound that has demonstrated strong proofs of concept in in-vivo and in-vitro types of epilepsy. It is designed to target and activate KCC2, a potassium chloride co-transporter credited for maintaining chloride balance in neurons. OV350 is thought to inhibit neuronal hyperexcitability, commonly linked with epilepsies, by improving homeostasis. Mutations and dysfunctions in KCC2 might be one of the contributors to seizures and epileptic symptoms. Why is there a Need for Epilepsy Cure? “Despite therapeutic advances in recent decades, approximately one-third to one-half of people who are treated for epilepsy continue to experience seizures. Therapies that activate KCC2, such as OV350, could become a powerful weapon for clinicians seeking to treat a potential underlying cause of epilepsies,” said Dr. Stephen Moss, one of the lead scientists at Tufts Laboratory for Basic and Translational Neuroscience Research, in a statement . Tufts Laboratory and AstraZeneca are collaborating to advance studies on OV350, with Dr. Moss joined by Dr. Jamie Maguire, who is also an expert in neuropharmacology on GABA receptor research. Harvard Medical School’s Dr. Aaron Goldman will also provide expertise in drug resistance to Ovid’s line of epilepsy and neurotherapeutic candidates. Data from pre-clinical studies show that OV350 may be developed to treat multiple types of epilepsy and other CNS conditions, including neurodegenerative and neurodevelopmental diseases. “The compounds are a natural fit for our franchise dedicated to small molecule epilepsy medicines, and they follow our track record of successful partnering with large pharmaceutical companies,” added Jeremy Levin, D.Phil, MB BChir, the chairman and chief executive of Ovid, in the same press release. OV350 is the latest addition to Ovid’s pipeline of anti-epileptic candidates. It is currently developing OV329, next-generation pregabalin for treating tuberous sclerosis and infantile spasms (expected to start clinical trials later this year), OV882, an RNA therapy approach to Angelman syndrome, and OV815, a gene therapy approach to KIF1A-linked neurological diseases. The company also licensed its novel cholesterol 24-hydroxylase inhibitor soticlestat to Takeda , which is being observed and is actively enrolling for Phase III studies for Lennox Gastaut and Dravet syndromes.