About

Samuel G. Jacobson, MD, PhD, is a faculty member at the Perelman School of Medicine at the University of Pennsylvania. He serves as the Director of the Center for Hereditary Retinal Degenerations and the Director of the Retinal Function Department at the Scheie Eye Institute. His educational background includes a B.A. in Humanities from the University of Illinois, an M.D. from the same institution, and a Ph.D. in Psychophysics from the University of London. His research focuses on hereditary retinal degenerations, with a particular emphasis on gene therapy, ciliary defects, and visual function in retinal diseases. He has contributed to understanding the molecular mechanisms underlying conditions such as X-linked retinitis pigmentosa, achromatopsia, and cone monochromacy, and has been involved in developing outcome measures for clinical trials and evaluating gene therapy approaches. His work includes investigating the toxicity and efficacy of gene delivery vectors and exploring structural and functional outcomes of late-stage gene therapy interventions.

Research topics

• Biology
• Medicine
• Ophthalmology
• Genetics
• Cell biology

Selected publications

• Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation–Effect of an ALG6 Modifier Variant

  International Journal of Molecular Sciences · 2024-01-13 · 4 citations

  articleOpen access

  Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.

  PublisherOA PDFDOI

• Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations

  iScience · 2024-10-28 · 1 citations

  erratumOpen access1st authorCorresponding

  [This corrects the article DOI: 10.1016/j.isci.2021.102409.].

  PublisherDOI

• Abstract TP179: Reversible Cerebral Vasoconstriction Syndrome (RCVS): A Retrospective Analysis of 79 Cases

  Stroke · 2024-02-01

  article1st authorCorresponding

  Background: RCVS is characterized by severe thunderclap headaches often triggered by medications or sexual activity. Convexity subarachnoid hemorrhage, and less commonly, ischemic stroke and intracerebral hemorrhage can occur. There are few studies of the clinical-imaging features of RCVS (Singhal, 2011; Ducros, 2007). The pathogenesis is yet to be understood, and further studies looking into various triggers and outcomes, such as our present one, is essential to characterize the condition and develop targeted treatments. Methods: We performed an EMR search (2012-2023) for patients over 18Y of age with a diagnosis of RCVS in inpatient and outpatient settings. We retrospectively analyzed clinical (demographics, triggers, and discharge mRS)) and imaging features (CTA, MRA, DSA, and transcranial doppler (TCD)) to confirm RCVS diagnosis. RCVS score was calculated. Discharge mRS was inferred from EMR. Diagnosis adjudication was performed by RSM. Student t-test and Chi-square test were used to analyze outcomes. Results: Seventy-nine patients were identified (mean age 40±11.5Y, 91% women). The most common triggers were medications (39%), sexual activity (11.4%), and marijuana use (5%). One-third (35%) had chronic headache history (migraines 22%). Twenty-nine (37%) were postpartum (n=19) or pregnant (n=10). Fourteen had concurrent pre-eclampsia (17%). Twelve (15%) also had imaging features of posterior reversible encephalopathy syndrome (PRES). Vasoconstriction was seen on DSA (n=15), CTA (n=25), and MRA (n=23); In 14 patients, vasoconstriction was evident only on TCD. SAH occurred in 26 (33%), ischemic stroke in 8, and ICH in 9. Median RCVS score was 7 (IQR 6-9, range 4-10). CSF profile (n=19) was normal, aside from mildly elevated lymphocyte count (n=2, range 10-13 cells) or protein (n=5, range 50-80 mg/dL). Discharge mRS was 0-1 in 83%. Patients without RCVS trigger (n= 40) had higher ischemic stroke or hemorrhage occurrence ( χ2 = 3.8, P=0.05 ). RCVS scores in pregnant/postpartum patients were similar to others ( t = 2.01, P = 0.06). Conclusion: In this case series, absence of an RCVS trigger was associated with occurrence of stroke or hemorrhage. Most patients had favorable prognosis. These findings need to be confirmed in prospective studies.

  PublisherDOI

• Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

  eLife · 2023-03-28 · 33 citations

  articleOpen access

  Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene CEP290 . We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in rd16 organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.

  PublisherDOI

• Author response: Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

  2023-02-19

  peer-reviewOpen access

  High-throughput screening of over 6000 drugs using cells and retina tissue with a CEP290 ciliopathy mutation identified a small molecule, reserpine, which enhanced photoreceptor survival in retinal organoids and in a mouse disease model by partially restoring balance in proteostasis.

  PublisherDOI

• Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: Replication in two eyes

  American Journal of Ophthalmology Case Reports · 2023-06-20 · 14 citations

  articleOpen access

  Purpose: gene. A previous report showed vision improvements following a single injection in one eye with unexpected durability lasting at least 15 months. The current study evaluated durability of efficacy beyond 15 months in the previously treated left eye. In addition, peak efficacy and durability were evaluated in the treatment-naive right eye, and re-injection of the left eye 4 years after the first injection. Observations: Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at ∼2 years, and returning to baseline by 3-4 years after each single injection. Conclusions and Importance: These results suggest that sepofarsen reinjection intervals may need to be longer than 2 years.

  PublisherDOI

• Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial

  Translational Vision Science & Technology · 2023-01-24 · 3 citations

  articleOpen access

  Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials. Methods: Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests. Results: All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities. Conclusions: Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM. Translational Relevance: Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease.

  PublisherOA PDFDOI

• Restoration of Cone Sensitivity to Individuals with Congenital Photoreceptor Blindness within the Phase 1/2 Sepofarsen Trial

  Ophthalmology Science · 2022-03-02 · 16 citations

  articleOpen access

  Purpose: ) gene. Design: Phase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial. Participants: A homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost. Intervention: Participants received a single intravitreal injection of sepofarsen (160 or 320 μg) into the study eye. Main Outcome Measures: Full-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection. Results: < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants. Conclusions: -associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.

  PublisherOA PDFDOI

• The landscape of submicroscopic structural variants at the <i>OPN1LW/OPN1MW</i> gene cluster on Xq28 underlying blue cone monochromacy

  Proceedings of the National Academy of Sciences · 2022-06-27 · 13 citations

  articleOpen access

  Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third ( n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families—all from the United States—showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no “region of overlap” among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.

  PublisherOA PDFDOI

• Night vision restored in days after decades of congenital blindness

  iScience · 2022-10-01 · 35 citations

  articleOpen access1st authorCorresponding

  units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thus possible in patients even after being disabled and dormant for decades.

  PublisherOA PDFDOI

Recent grants

• NIH Grant U10EY017280

  NIH · $9.8M · 2016

• NIH Grant R01EY013385

  NIH · $2.0M · 2007

• NIH Grant R01EY005627

  NIH · $2.8M · 2002

Frequent coauthors

• Artur V. Cideciyan

  University of Pennsylvania

  964 shared

• Alexander Sumaroka

  University of Pennsylvania

  392 shared

• Alejandro J. Román

  366 shared

• Tomas S. Alemán

  University of Pennsylvania

  342 shared

• Sharon Schwartz

  University of California, Santa Cruz

  310 shared

• Edwin M. Stone

  294 shared

• Małgorzata Świder

  Penn Presbyterian Medical Center

  210 shared

• Elise Héon

  Hospital for Sick Children

  167 shared

Education

• Retinal Degeneration Fellow, Massachusetts Eye and Ear Infirmary

  Harvard Medical School

  1983

• Honorary Clinicial and Research Assistant, Institute of Ophthalmology, Neuro-ophthalmology Service

  Moorfields Eye Hospital

  1982

• Honorary Clinical and Research Assistant, Vision Research Unit

  St. Thomas' Hospital

  1982

• Resident in Ophthalmology, Massachusetts Eye and Ear Infirmary

  Harvard Medical School

  1980

• Research Affiliate, Department of Psychology

  Massachusetts Institute of Technology

  1980

• Ph.D., National Hospital, Queen Square, UCL

  University Of London

  1977

• Honorary Clinical Assistant, National Hospital, Queen Square

  University of London

  1977

• Intern, Internal Medicine

  Rush-Presbyterian St.Luke's Medical Center

  1971

• M.D., College of Medicine

  University of Illinois at Chicago College of Medicine

  1970

• B.A., English Literature

  University of Illinois at Chicago

  1966