Author: Trim, Paul J ; Hemsley, Kim M ; Lance, Tabitha-Rose ; Scott, William ; Mubarokah, Siti N ; Lau, Adeline A ; Winner, Leanne ; Parkinson-Lawrence, Emma ; Snel, Marten F ; King, Barbara ; Shoubridge, Andrew ; Beard, Helen

BACKGROUNDSanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness.AIMTo compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.METHODSNeonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out.RESULTSBoth treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery.CONCLUSIONSConfirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life.

01 Apr 2023·Gene Therapy

IgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice

Article

Author: Nicely, Nathan I ; Fu, Haiyan ; Robinson, Michael I ; Bobo, Tierra A ; Samowitz, Preston N ; Feng, Richard ; Forsberg, Lawrence J ; Montes, Laura I

The widespread pre-existing αAAV-Abs in humans pose a critical challenge in translation of AAV gene therapy. The IgG degrading enzyme of Streptococci (IdeS) is demonstrated to specifically cleave IgG of humans and other species (not mouse). This study developed a modified new modified IdeS protein product (IdeS^op). When incubated in vitro, IdeS^op was shown to completely cleave human and rabbit IgGs within 6 h. To test IdeS^op in a disease setting, we established a rabbitized αAAV9-Ab⁺ mouse by an IV infusion of purified acute αAAV9-Ab⁺ rabbit IgG into MPS IIIA mice, resulting in serum αAAV9-IgG at 1:6,400 and αAAV9-nAbs at 1:800. IdeS^op-Ab-cleavage was shown to be dose-dependent. An IV IdeS^op infusion at the effective doses resulted in rapid IgG depletion and clearance of pre-existing αAAV9-IgG and αAAV9-nAbs in rabbitized αAAV9-Abs⁺ MPS IIIA mice. Importantly, an IV injection of a high dose AAV9-hSGSH^op vector (5 × 10¹³vg/kg) at 24 h post IdeS^op treatment led to transduction as effective in αAAV9-Abs⁺ MPS IIIA mice, as in αAAV9-Abs-negative controls. We believe that transient IdeS^op administration may offer a great tool to address the pre-existing-αAAV-Abs for the translation of rAAV gene therapy to treat diseases in humans, making effective rAAV gene therapy available to all patients in need.

01 Dec 2020·Acta Neuropathologica CommunicationsQ2 · MEDICINE

Is the eye a window to the brain in Sanfilippo syndrome?

Q2 · MEDICINE

ArticleOA

Author: Snel, Marten F ; Beard, Helen ; Douglass, Meghan ; Neumann, Daniel ; Hemsley, Kim M ; Casson, Robert J ; Chidlow, Glyn ; Trim, Paul J ; Nazri, Nazzmer

AbstractSanfilippo syndrome is an untreatable form of childhood-onset dementia. Whilst several therapeutic strategies are being evaluated in human clinical trials including i.v. delivery of AAV9-based gene therapy, an urgent unmet need is the availability of non-invasive, quantitative measures of neurodegeneration. We hypothesise that as part of the central nervous system, the retina may provide a window through which to ‘visualise’ degenerative lesions in brain and amelioration of them following treatment. This is reliant on the age of onset and the rate of disease progression being equivalent in retina and brain. For the first time we have assessed in parallel, the nature, age of onset and rate of retinal and brain degeneration in a mouse model of Sanfilippo syndrome. Significant accumulation of heparan sulphate and expansion of the endo/lysosomal system was observed in both retina and brain pre-symptomatically (by 3 weeks of age). Robust and early activation of micro- and macroglia was also observed in both tissues. There was substantial thinning of retina and loss of rod and cone photoreceptors by ~ 12 weeks of age, a time at which cognitive symptoms are noted. Intravenous delivery of a clinically relevant AAV9-human sulphamidase vector to neonatal mice prevented disease lesion appearance in retina and most areas of brain when assessed 6 weeks later. Collectively, the findings highlight the previously unrecognised early and significant involvement of retina in the Sanfilippo disease process, lesions that are preventable by neonatal treatment with AAV9-sulphamidase. Critically, our data demonstrate for the first time that the advancement of retinal disease parallels that occurring in brain in Sanfilippo syndrome, thus retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored.

News (Medical) associated with EGT-101

04 Feb 2023

·www.prnewswire.com

Egret Therapeutics Receives FDA Clearance of IND Application for EGT 101 for Treatment of Delayed Cerebral Ischemia

Egret Therapeutics, a portfolio company of Turret Capital Management, announces FDA Clearance of its IND Application for EGT 101 NEW YORK, Feb. 4, 2023 /PRNewswire/ -- Egret Therapeutics, a clinical-stage biotechnology company focused on developing transformative therapies for neurological conditions, today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for EGT 101 that is being studied for the treatment of Delayed Cerebral Ischemia (DCI) following aneurysmal subarachnoid hemorrhage. The Phase I/II trial is expected to begin enrolling patients in 2023. "We are thrilled to have received IND clearance for our program in aneurysmal subarachnoid hemorrhage," said Daniel Chai, M.D., Co-Founder and Chief Executive Officer of Egret Therapeutics. "Clearance of this IND is a testament to the hard work and deep commitment from the Egret team in bringing drugs to the market that will help patients," said Henry Park, Chief Financial Officer of Egret Therapeutics. Among subarachnoid hemorrhage (SAH) patients who survive the initial bleed of a ruptured aneurysm, delayed cerebral ischemia (DCI) is the most important preventable cause of mortality and poor neurological outcome. "DCI prevention has been the focus of SAH research for decades, but few clinical options exist today. We are excited to move forward in our clinical development of EGT 101 with the hopes of bringing a therapy to patients where there is a high unmet need," said Chris Jackson, M.D., Co-Founder and Chief Medical Officer of Egret Therapeutics. About Egret Therapeutics Egret Therapeutics is a clinical-stage biotherapeutics company. The company is focused on developing products to address areas of clinical unmet need in neurological diseases. For more information, visit us at SOURCE Turret Capital Management

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Indication	Highest Phase	Country/Location	Organization	Date
Mucopolysaccharidosis III	Phase 2	-	Universitat Autònoma de Barcelona	-

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