Category Archives: Gene therapy

Cell and gene therapies (CGTs), also classified as Advanced Therapy Medicinal Products (ATMPs), have been hailed as revolutionary, but the path towards realising their potential has also seen pitfalls and disappointments along the way since the first attempts some decades ago.

Today, CGTs offer new horizons for people living with some rare, lifelong diseases. However, despite their promise, these therapies entail a range of scientific, logistic, regulatory and economic challenges. There is a clear need for inclusive dialogue to define a way forward in ensuring safe and affordable access to these novel treatments.

The current landscape: hopes and hurdles

In several disease areas, CGTs already exist and have transformed patients lives. Speaking at a debate convened by the European Health Forum Gastein and CSL Behring on 15th of June, Avril Daly (EURORDIS) stressed that we often think about CGTs as futuristic products, while they are already being administered in the now.

Thus, a main objective should be providing access for patients and their families and turning hope into reality. Bertalan Mesk (Medical Futurist Institute) reinforced this notion by urging to make patients the point of care and involve them at the highest level of decision-making.

However, where there are expectations and hope, there are also concerns and uncertainties.

Speaking in a personal capacity, Ilona G. Reischl (Austrian Medicines and Medical Devices Agency), commented that she sees a trivialisation of CGTs in Europe: we are discussing complex medicinal products and CGTs should be treated as such, she emphasised, underlining that there is a need for appropriate regulation and for clinical trials in order to provide product specific information.

It is also crucial to collect real-world data to help answer important questions about the durability of treatment responses to CGTs and to inform novel payment approaches for potentially curative, one-off therapies.

Further, health systems must adapt to accommodate this paradigm shift in care as they have done previously with ground-breaking, disruptive medical innovations.

Pooling expertise, setting up clinical frameworks and providing the means and infrastructures to enable the specialist care needed to deliver CGTs is now top of the agenda.

Equally important is ensuring appropriate infrastructure and processes to access diagnosis and genetic testing, as a first step for patients in receiving these transformative therapies.

However, time is of the essence for patients with rare diseases lacking treatment options or with poor quality of life. Opportunities to provide therapies that save, change or enhance these patients lives cannot be missed.

What may be seen as a small improvement can in fact have a huge impact of patients quality of lives, and the way we measure improvements need to change to reflect properly patients experiences and expertise, noted Avril Daly.

If indeed CGTs will transform tomorrows healthcare paradigm, we are not far from tomorrow, explained Dan Hart (Royal London Hospital Haemophilia Centre). The scientists have done the work, and it is now up to us to overcome some of the ethical implications linked with ensuring equal access across Europe.

Several EU policy initiatives offer possibilities to define a European policy and regulatory environment that addresses current challenges and is future-proof with respect to embracing medical innovation and ensuring patient access while maintaining European leadership in this field.

These include the upcoming EU Pharmaceutical Strategy, the European Health Data Space (EHDS), and the evaluation/revision of existing legislation including the EU Cross-border Healthcare Directive and the EU Blood, Tissues and Cells Directive. Andrzej Ry (European Commission Directorate General for Health and Food Safety), stressed the need for continuity and for legislation that is adaptable and reduces administrative burden.

Alignment between the relevant EU legislation and between European and national frameworks will be paramount, said Ilona G. Reischl, including rules on hospital exemption (HE) which allow for the use of an ATMP without a marketing authorisation under certain circumstances.

The willingness of all to realise ATMPs is there, and the stars are aligned, said Ry, while MEP Cristian Silviu Buoi outlined that by 2025 the European Medicines Agency shall approve 10-20 CGTs annually.

Paige Bischoff (Alliance for Regenerative Medicine) reflected on the fact that the EU Pharmaceutical Strategy refers to ATMPs as a major milestone of innovation. What is key now is greater harmonisation across Europe to support the Strategy, especially in legislation regulating genetically modified organisms (GMOs).

The EHFG debate revealed a consensus that allowing creativity and flexibility at all levels can help provide an environment where patients can best benefit from CGT. For example, legislative frameworks need to be adaptable to innovation, and COVID-19 served as an example of how to adapt quickly to change.

From a pricing and reimbursement perspective, new payment models are needed to reflect the novel features of CGTs. One size will not fit all, as every CGT is different. Diane Kleinermans (Belgian National Institute for Health and Disability Insurance) highlighted that thinking out of the box will be important to answer to the needs inherent to new technologies and therapies.

Further, international cooperation is the way forward, and the BeNeLuxA initiative is one example of this, she explained, as a platform for collaboration between five countries to monitor the whole life spectrum of medicines, organise joint Health Technology Assessments and conduct horizon scanning.

EU-level support for the continuous monitoring of quality and harmonised data, including via the EHDS, will be a building block to guarantee patient access to safe and effective CGTs across Europe and to address burning questions such as how safe is safe enough, or when health systems should pay for treatment given uncertainties in the durability of patient responses.

Reducing fragmentation, standardising data across borders and the increased use of real-world evidence will be key to supporting the acquisition of longer-term data, Bischoff asserted.

Cooperation between medical experts, policymakers, regulators, hospitals and academic developers, patients, health technology assessors, payers and industry will be decisive in transforming healthcare. Advancing CGTs requires collaboration as well as patient-centricity, working with and for patients.

The field of CGTs is deeply complex, as outlined by Vivienne Parry, science writer and broadcaster, and facilitator of the debate but the fact is that CGTs are real and being administered now.

They disrupt traditional ways of providing healthcare, of developing, assessing and paying for treatments, and challenge us all to rethink existing policies and practices or, as Bertalan Mesk pointed out at the beginning of the debate, to shift mindsets to incorporate change, as technological adoption needs to be accompanied by cultural adoption.

This article reflects on a more extensive discussion that took place during the webinar Transforming the future of healthcare do cell and gene therapies hold the key?, organised by the European Health Forum Gastein and CSL Behring on 15th June 2021. Ilona Reischl and Diane Kleinermans spoke in a personal capacity during this meeting. To watch the recording of this webinar, please visit https://www.youtube.com/watch?v=QL6OYmoJIzg

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Transforming healthcare: do cell and gene therapies hold the key? - EURACTIV

This webcast features: Jared Isaac, PhD, Sr. Scientist, Chromatography and Mass Spectrometry, Cygnus Technologies

Next-generation recombinant vaccines and gene therapy products require clinical and commercial manufacturing of protein antigens or viral vectors produced using cell culture technologies. Regulatory guidelines require testing for cell substrate related impurities, media and purification additives, as well as adventitious agents throughout vaccine and gene therapy development to study the candidates purity, safety, and efficacy. While low levels of most impurities can be inconsequential, patient safety demands that host cell proteins (HCPs) be eliminated or reduced to the lowest levels practical. A key step in downstream purification of viral vectors and recombinant vaccines is the selection of a platform HCP enzyme-linked immunosorbent assay (ELISA) kit or developing a custom HCP ELISA. One part of determining that the ELISA is fit for purpose is performing antibody coverage analysis.

In this webinar, we will discuss orthogonal Antibody Affinity Extraction and Mass Spectrometry methods used to assess ELISA Ab coverage to HCPs present in a process and identify process-specific HCPs that may copurify with a drug substance. Case studies of HEK 293, Sf9, and Vero cell-based processes will be presented.

Just fill out the form below to watch the recorded webcast.

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HCP Analysis by ELISA and Orthogonal Methods in Vaccine and Gene Therapy Development - BioProcess Insider

A clinical study of Bedford-based Nanoscope Therapeutics one-size-fits-all gene therapy for a rare genetic retina disorder meaningfully improved sight for 11 blind patients, according to the company.

The proprietary therapy delivers multi-characteristic opsin an optically activated protein similar to a molecular solar cell to retinal cells, and can be used to treat an array of diseases.

Nanoscope said it now believes its trial results are long-lasting, possibly improving vision for the patients entire lives. The optimism is based on observing the 11 patients progress for 52 weeks following the trial.

Classic gene therapy can only treat one disease at a time and there are hundreds of genes responsible for causing blindness. Optogenetic gene therapy can target hundreds of different diseases, including retinitis pigmentosa, age-related macular degeneration and Stargardt disease, all with a single product.

The therapy requires no retinal implants, invasive surgeries or goggles. Instead, the gene therapy is administered in a doctors office by a single injection through the eye.

Samarendra Mohanty, co-founder and president of Nanoscope Therapeutics, explained that genes are delivered to the retina, not photoreceptors, because in this instance photoreceptors like rods and cones are already destroyed.

The gene therapy transforms retinal cells into new photoreceptors.

Its like installing a solar panel on your house, on top of your roof ... you get [a] current generated for using in a home, Mohanty said. [Its the] same way the eye needs the current to send to [the] brain.

The year-long study began in 2018. Patients who had no vision at all were selected to participate in 2019. Initial results from the study were reported by the company last year, revealing that all patients experienced improved visual acuity at 16 weeks. All also saw a greater than 90% improvement in accurately describing shapes.

They used to come with their family member or chaperone, co-founder and CEO Sulagna Bhattacharya said about patients in the clinical trial. By 16 weeks, people start[ed] coming all by themselves. Of course, not driving the car, but taking public transportation, she said.

Patients were able to take over daily chores and activities that they could not do alone prior to the gene therapy treatment, the company said.

Nanoscope Therapeutics can now begin studying its gene therapy through a randomized test, which has potential to become pivotal, Mohanty said. The companys goal is to make the treatment available globally at an affordable price.

Current gene therapies can cost $3 million or more, Bhattacharya said. We want to make sure that regular people can afford it because its one drug applicable for so many patients, she said.

The drugs wide range of applications means it can be mass-produced, increasing affordability, Bhattacharya said.

Nanoscope Therapeutics is a spin-off from Nanoscope Technologies, a Bedford company founded in 2009 that has gotten backing from the National Institutes of Health. Nanoscope Therapeutics received a $2 million grant from the National Eye Institute in June 2020, and landed an undisclosed funding round a month later.

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Bedford biotechs gene therapy improves sight for 11 patients with a rare genetic retina disorder - The Dallas Morning News

Collaboration to Support AavantiBios Diverse Gene Therapy Pipeline; Development and Supply of GMP Cell Lines and Viral Banks

Agreement to Include Manufacture and Supply of Material for GLP Tox Studies and Clinical Trial for Friedreichs Ataxia Patients

CAMBRIDGE, Mass. & SAN DIEGO, Calif.--(BUSINESS WIRE)-- AavantiBio, a gene therapy company focused on transforming the lives of patients with rare genetic diseases, and National Resilience, Inc. (Resilience), a company building the worlds most advanced biopharmaceutical manufacturing ecosystem, today announced a strategic collaboration to support the development and manufacturing of AavantiBios pipeline of therapies, including its lead program in Friedreichs Ataxia (FA).

Resilience will provide process development and GMP manufacturing services including cell lines and viral banks for AavantiBios adeno-associated viral (AAV) vector-based therapeutic FA candidate for use in both pre-clinical studies, and Phase I/II clinical trials in the U.S. and Europe. Resilience will assist in the development and optimization of the manufacturing processes for GLP Tox and first-in human material at its 183,000-square-foot, state-of-the-art facility in Alachua, Florida.

"This partnership supports our immediate and long-term objectives in developing and ultimately commercializing our diverse pipeline of gene therapies, beginning with our lead FA program, said Bo Cumbo, President and Chief Executive Officer of AavantiBio. With an emphasis on Chemistry, Manufacturing and Controls (CMC) for gene therapies, we are committed to ensuring the quality of manufacturing processes along with analytical development. We look forward to a lasting collaboration with Resilience as we execute on our mission of bringing new therapies to patient populations."

We are excited to work with an innovative development-stage company like AavantiBio who is utilizing a unique AAV approach to address the underlying causes of rare genetic diseases, said Rahul Singhvi, Sc.D, Chief Executive Officer of Resilience. Our highly-experienced team will work collaboratively with AavantiBio on process development and analytical testing to enable a seamless transition from development to manufacturing.

FA is a rare inherited neuromuscular disease that causes progressive nervous system damage and movement problems. The multisymptomatic disease usually begins in childhood and leads to degeneration in the spinal cord, peripheral nerves and cerebellum (the part of the brain that controls synchronization and balance) and causes impaired muscle coordination (ataxia) that worsens over time. The neurological degeneration caused by the disease results in unsteady movements, impaired sensory function, and even the loss of speech. Affected individuals can also develop heart problems, diabetes, or curvature of the spine. Though rare, FA affects 1 in every 40,000-50,000 people and is the most common form of hereditary ataxia in the United States.

About AavantiBio, Inc.

AavantiBio is a gene therapy company backed by a premier syndicate of life sciences investors including Perceptive Advisors, Bain Capital Life Sciences, and RA Capital Management, who led the companys recent $107 million Series A financing. Headquartered in Cambridge, Massachusetts, AavantiBio is advancing a diversified gene therapy pipeline in areas of high unmet medical need, including a lead program in Friedreichs Ataxia, a rare inherited genetic disease that causes cardiac and central nervous system dysfunction. The company benefits from strategic partnerships with the University of Floridas renowned Powell Gene Therapy Center and the MDA Care Center at UF Health where AavantiBios co-founders and renowned gene therapy researchers Barry Byrne, M.D., Ph.D. and Manuela Corti, P.T., Ph.D. maintain their research and clinical practices. Learn more at http://www.aavantibio.com.

About Resilience

Resilience (National Resilience, Inc.) is a first-of-its-kind manufacturing and technology company dedicated to broadening access to complex medicines and protecting biopharmaceutical supply chains against disruption. Founded in 2020, the company is building a sustainable network of high-tech, end-to-end manufacturing solutions to ensure the medicines of today and tomorrow can be made quickly, safely, and at scale. Resilience offers the highest quality and regulatory capabilities, and flexible and adaptive facilities to serve partners of all sizes. By continuously advancing the science of biopharmaceutical manufacturing and development, Resilience frees partners to focus on the discoveries that improve patients lives. For more information, visit http://www.Resilience.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210603005247/en/

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AavantiBio and Resilience Announce Strategic Collaboration for Gene Therapy Development and Manufacturing - BioSpace

When Iveric Bio established its gene therapy advisory committee recently, the move signaled the opening of a second front in its mission to treat retinal diseases for which there are no treatments.

Retinal medicine is an extremely nuanced field, so we needed the best of the best scientists and clinicians out there, said Pravin U. Dugel, M.D., president of Iveric Bio. We established the committee once the basic science matured. Now were at the precipice of putting retinal gene therapy into humans.

The mission of the Gene Therapy Inherited Retina Disease Scientific Advisory Committee is to translate the science to the clinic.

A lot of companies miss the translation aspect. Just because the science is valid in the lab and in pre-clinical studies, doesnt necessarily mean it will be adapted to the clinic, Dugel told BioSpace.

The committees insights also will help us prioritize our pipeline and design clinical trials to be more impactful, he added. For example, determining clinical impact isnt as simple as checking vision. The visual acuity, which is a measure only of the central retina, may not improve in first-in-human studies and may not be the appropriate biomarker for some diseases.

Instead, better trial endpoints may be multi-luminance mobility testing, microperimetry, quality of life questionnaires, etc., depending on the target disease. Choosing the appropriate biomarkers, such as reading speed, contrast sensitivity, or other elements would offer meaningful improvements to people who are going blind. Also, the factors that are meaningful to an 85-year-old patient may be different than those of a 14-year-old, he pointed out.

Iveric Bio was founded by retinal specialists. Before joining Iveric Bio 18 months ago and recently becoming president of the company, Dugel himself was a practicing retinal specialist and remains an internationally known physician.

He is a clinical professor at the USC Roski Eye Institute, Keck School of Medicine, University of Southern California; has served as a visiting professor in some 16 nations; and has been the principal investigator in more than 100 multicenter trials. He received the Senior Honor Award from the American Academy of Ophthalmology and has served as a board member for the largest retina society in the United States, the American Society of Retina Specialists (ASRS), and the largest retina society in Europe, EURETINA.

In selecting the gene therapy advisory committee, therefore, we werent starting from scratch. The retinal world is small. There are only 2,500 retinal specialists in the U.S., and everybody knows everybody. They each have a certain niche, he said.

Dugel has worked with many of these committee members before joining the company and has known many throughout his professional life. This collegiality is expected to enhance Iveric Bios gene therapy program.

Members of the new Gene Therapy Inherited Retina Disease Scientific Advisory Committee are:

The gene therapy program on which they are advising currently has five different products, all in the pre-clinical and research phases. The furthest along are IC-100 for RHO-adRP and IC-200 for best1-related retinal diseases. For IC-200, a Phase I/II trial is planned for the second half of this year.

The remaining programs are miniCEP290 for Lebers congential amaurosis type 10; miniABDA4 for autosomal recessive Stargardt disease; and miniUSH2A for Ushers syndrome Type 2A. They are dubbed mini-gene programs because, in these programs, the naturally occurring gene is larger than the capacity of the standard adeno-associated viral (AAV) vector used for gene therapy. Iveric Bio, therefore, is working to develop smaller gene constructs to enable AAV gene delivery.

The company also has two therapeutic product candidates in development. One, Zimura (avacincaptad pegol), is in development for the treatment of geographic atrophy secondary to macular degeneration.

Zimura currently is being studied in a Phase III clinical program, and if results at 12 months are positive, we plan to submit Zimura to the FDA for final approval in this indication, Dugel said.

Zimura also is in a Phase IIb clinical trial to treat autosomal recessive Stargardt disease.

The other product candidate, IC 500, is an HtrA1 inhibitor. It is designed to stop the progression of macular degeneration and is in preclinical development.

When I entered this field, about 30 years ago, treatments for retinal diseases were almost entirely surgical. We couldnt do anything for macular degeneration or most inherited diseases. We could repair retinal detachments, but were unable to treat most of the medical problems we encountered, Dugel recalled. Since then, theres been astonishing progress in this field.

Many of the advances have been in wet macular degeneration.

Were not doing that. We are focusing on diseases for which there is no treatment, Dugel told BioSpace. Retinal conditions with unmet needs are not necessarily rare, either. The biggest cause of blindness is dry macular degeneration, yet theres no treatment for that.

Hes hoping Zimura will solve that.

These two silos, therapeutics and gene therapy, will help Iveric Bio expand its footprint in the retinal arena. The ultimate goal is to uphold Iveric Bios mission statement: to develop transformative therapies for retinal diseases.

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Iveric Bio Expands into Gene Therapy for Untreated Retinal Diseases - BioSpace

Beginning this week, the U.S. Food and Drug Administration (FDA) ended its compliance and enforcement discretion policy with regard to certain human cell, tissue, and cellular and tissue-based products (HCT/Ps). HCT/P manufacturers without an FDA-approved marketing application may find themselves subject to FDA scrutiny under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act). Firms will have to think hard about whether to submit investigational new drug applications (INDs) or marketing applications, wind down production, or risk running afoul of applicable laws and regulations governing unapproved biological products. They should also be mindful of how data collected to date can help to inform next steps.

HCT/Ps are articles containing or constituting human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.1 They are regulated under sections 351 and 361 of the PHS Act and/or the FD&C Act and implementing regulations.2 Generally, HCT/Ps will have undergone substantial manufacturing, and clinical data will be necessary in order to establish the safety and effectiveness of these products prior to marketing.3 However, there are two exceptions to this general rule. First, FDA will exempt HCT/Ps from the premarket review and approval processes and regulate them exclusively under section 361 if they:

Second, FDA has explained that it views autologous cells or tissues that are removed from an individual and implanted into the same individual without intervening processing steps beyond rinsing, cleansing, sizing, or shaping to raise no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery.5 As such, premarket review and other regulatory requirements will not apply to an HCT/P that is removed and reimplanted in its original form in the same individual during the same surgical procedure.6

In the fall of 2017, FDA announced a temporary compliance and enforcement discretion policy, under which FDA applied a risk-based approach to enforcement actions for HCT/P manufacturers whose products were subject to the premarket review process but did not yet meet regulatory requirements.7

The enforcement discretion did not mean that FDA was turning a completely blind eye to HCT/P manufacturers that were marketing unapproved products. Indeed, the Agency stated its intent to take enforcement action against products that had safety concerns reported or that FDA believed had the potential to raise safety concerns. Thus, notwithstanding the enforcement discretion policy, FDA focused its enforcement actions on HCT/Ps that posed a higher risk, as measured by the products route of administration and the diseases and conditions for which they were being used,8 and issued at least 14 warning letters and 24 untitled letters to HCT/P manufacturers during the enforcement discretion period.9 And, in a potential preview of things to come, FDA also sent approximately 400 it has come to our attention letters to various health care providers, clinics, and manufacturers of cellular products, alerting them that they may be marketing unapproved HCT/Ps and subject to FDAs compliance and enforcement policy.10

FDA initially intended the compliance and enforcement policy to last three years (through November 2020) to afford HCT/P manufacturers time to comply with the premarket approval requirements.11 In July 2020, FDA extended the compliance and enforcement policy through May 31, 2021.12 Leaders at the Agency, including Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER), and Melissa Mendoza, Deputy Director for CBERs Office of Compliance and Biologics Quality, confirmed that the policy would not be extended beyond May 31, 2021.13 The compliance and enforcement discretion policy is now over.

Beginning on June 1, 2021, manufacturers of cell and gene therapy HCT/Ps that do not hold an approved marketing application or fall within one of the two exempt categories described above, are operating at risk of violating the PHS Act and/or FD&C Act. Ultimately, such manufacturers need to engage with FDA, and in particular with CBER, to determine the path to an approved marketing application. In most cases, this means submitting a biologics license application (BLA) under section 351(a) of the PHS Act. This type of BLA, known as a stand-alone BLA, will need to include (among other things) all of the data and information necessary to establish the ongoing quality, safety, purity, and potency of the HCT/P for its intended uses.14 It will be particularly important for manufacturers of HCT/Ps to consider what data they may have collected through real world use of their products to date, including during the period of enforcement discretion, and how that data may be able to be used to support approval of their BLAs. The rapidly evolving chemistry, manufacturing, and controls (CMC) standards and guidance for cell and gene therapy products should be consulted for important context.15 An acceptable manufacturing facility inspection is typically required before a BLA can issue,16 and many inspections have been significantly delayed during the current COVID-19 public health emergency.17

The first step toward compliance generally will be to open an IND to conduct clinical trials in support of such a BLA, and to engage in discussion with FDA regarding appropriate submission of a marketing application. In addition to standard BLA-focused meetings under the Prescription Drug User Fee Act (PDUFA), including initial pre-IND meetings,18 CBERs Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) meeting process allows for informal preliminary advice before the pre-IND phase.19

HCT/Ps also may qualify for designation as regenerative medicine advanced therapies (RMAT). This designation, which must be granted by FDA, can be requested either concurrently with an IND submission or by amending an existing IND. Cell therapies, therapeutic tissue engineering products, human cell and tissue products, certain human gene therapies and xenogeneic cell products, and combination products that include such therapies or productsother than HCT/Ps that fall within an exception and are regulated solely under section 361 of the PHS Actwill be eligible for RMAT designation if they are intended for serious or life-threatening disease or conditions, and preliminary clinical evidence indicates the potential to address unmet medical needs.20 RMAT-designated products will receive the benefits of fast track and breakthrough therapy designation, including early interactions with FDA that can be used to discuss potential surrogate or intermediate endpoints to support accelerated approval.21 This can also mean fewer COVID-19-related inspection delays.22 RMATs may also receive priority review if they are intended to treat serious conditions and, if approved, would provide a significant improvement in the safety or effectiveness of the treatment of the condition.23 RMATs also may be appropriate for approval through the accelerated approval pathway, and there may be additional benefits in terms of fulfilling associated post-approval requirements.24

Importantly, though, even active discussions with FDA will not preclude enforcement action, including issuance of warning and untitled letters, and potentially injunctions,25 civil monetary penalties,26 and seizure.27 FDA has made clear that, for products that do not fall within one of the exempt categories, the risk of enforcement can be averted only by obtaining approval of a marketing application.28 In fact, last month, CBER Director Marks drew a red line: Such products should not be marketed without FDA approval.29

Manufacturers of cell and gene therapy HCT/Ps without FDA approval can take discrete steps to mitigate the risk of regulatory enforcement. Specifically, manufacturers should carefully review the applicability of exemptions from premarket review requirements to their HCT/Ps and consider if their products or distribution processes can be restructured to align with the exemptions. Where appropriate, manufacturers should prioritize engaging with FDA and initiating concrete steps toward preparing marketing applications. They should also ensure that, in the meantime, their HCT/Ps are used only under an IND. Alternately, manufacturers may consider winding down operations, particularly if the likelihood of obtaining an approval or qualifying for an exemption proves infeasible. If manufacturers choose to continue existing operations without taking corrective action, they operate at risk of FDA enforcement.

1 21 C.F.R. 1271.3(d).

2 FDA, Guidance for Industry, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use at 34 (July 2020), https://www.fda.gov/media/109176/download [hereinafter HCT/P Guidance]; see also 21 U.S.C. 355(a); 42 U.S.C. 262(a); 21 C.F.R. Part 1271.

3 See 42 U.S.C. 262(a) and 264; 21 C.F.R. 601.2(a).

4 See 21 C.F.R. 1271.10(a); HCT/P Guidance, at 3.

5 FDA, Guidance for Industry, Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception at 3 (Nov. 2017), https://www.fda.gov/media/89920/download.

6 See 21 C.F.R. 1271.15(b).

7 See HCT/P Guidance, at 22 n.32.

8 FDA, Press Release, FDA Announces Comprehensive Regenerative Medicine Policy Framework (Nov. 15, 2017), https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework.

9 Melissa Mendoza, Deputy Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, Address at the Food and Drug Law Institute: Key Issues in Regenerative Medicine Regulation and Approval (May 18, 2021).

10 Id.; see also Peter Marks, Advancing the Development of Safe and Effective Regenerative Medicine Products, U.S. Food & Drug Admin. (Apr. 21, 2021), https://www.fda.gov/news-events/fda-voices/advancing-development-safe-and-effective-regenerative-medicine-products.

11 See 82 Fed. Reg. 54290, 5429192 (Nov. 17, 2017); HCT/P Guidance at 22 n.32.

12 See HCT/P Guidance at 12.

13 See Peter Marks, Director, Center for Biologics Evaluation and Research, Address at the Food and Drug Law Institute: Center for Biologics Evaluation and Research (CBER) Session (May 20, 2021); see also Mendoza, supra note 9, Marks, supra note 10.

14 See 42 U.S.C. 262(a); see also 21 C.F.R. 601.2(a); HCT/P Guidance at 34.

15 See 85 Fed. Reg. 5447, 544748 (Jan. 30, 2020); FDA, Guidance for Industry, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (Jan. 2020); see also FDA, Cellular and Gene Therapy Guidances, https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances (last updated Jan. 5, 2021) (providing directory to other FDA cellular and gene therapy guidance documents).

16 42 U.S.C. 262(c); 21 C.F.R. 601.20(d).

17 See FDA, Resiliency Roadmap for FDA Inspectional Oversight at 2 (May 2021), https://www.fda.gov/media/148197/download.

18 See FDA, Draft Guidance for Industry, Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products at 3 (Dec. 2017), https://www.fda.gov/media/109951/download.

19 See FDA, INTERACT Meetings, https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings (last updated July 9, 2020).

20 21 U.S.C. 356(g).

21 Id.; FDA, Guidance for Industry, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions at 6 (Feb. 2019), https://www.fda.gov/media/120267/download [hereinafter RMAT Expedited Programs Guidance].

22 See Resiliency Roadmap for FDA Inspectional Oversight, supra note 17, at 2 (RMAT-designated products are considered mission-critical for inspection prioritization).

23 See RMAT Expedited Programs Guidance at 9.

24 21 U.S.C. 356(g)(6)(7); RMAT Expedited Programs Guidance at 911.

25 See 21 U.S.C. 332(a) and 331(a)(b).

26 See id. 333(a).

27 See id. 334(a).

28 See Mendoza, supra note 9 (At this point, thats not good enough to avoid potential compliance or enforcement action. So please, please do not count on any enforcement discretion going forward.)

29 See Marks, supra note 13.

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The End of Enforcement Discretion for Cell & Gene Therapies: Thinking Through Next Steps - JD Supra

On Jun 3, 2021

A geneticist with Morristown-based Atlantic Health Systems physician network, Atlantic Medical Group, recently treated the first patient in the United States in a clinical trial with a genetic therapy developed by BioMarin, designed to help patients who are not able to metabolize phenylalanine, an amino acid found in nearly all proteins.

Darius Adams, MD, medical director of the Jacobs Levy Genomic Medicine and Research Program at Atlantic Health System and division chief of pediatric genetics, provided the therapy as part of a clinical trial that includes Atlantic Health System and currently two other hospitals worldwide.

The investigational therapy was given intravenously to an adult diagnosed with phenylketonuria(PKU), a genetic disorder that affects people from birth. The patient will be monitored for five years to determine the long-term safety and efficacy of the treatment.

We are excited to be on the forefront of studying this new therapy that could radically improve the lives of so many people, said Dr. Adams. The impacts of phenylketonuria stretch further than simply dietary concerns, and this therapy offers great promise to these individuals to possibly having a better quality of life, throughout their lifetime.

Dr. Adamss work is supported by his colleagues, Christina Flora, research coordinator, and Lindsay Schumacher, dietician.

Newborn screeningbegan with the development of a blood test for phenylketonuria in the 1960s. The test was given to babies soon after birth, in order to allow physicians and dietitians to begin dietary therapy as needed as soon as possible.

While a certain amount of phenylalanine is needed by the body, an overabundance of it can cause a range of problems, from behavioral and intellectual disorders, to severe brain damage.

To date, patients who have PKU have had limited treatments available to them, primarily in the form of specific dietary restrictions that begin in a persons infancy or daily injections when older. Due to an abundance of carbohydrates replacing protein in these altered diets, obesity can often be a side effect. Maintaining these restrictions can become challenging later in life, such as during college years and depending upon a persons profession in adulthood.

The disorder is caused by a genetic mutation in a persons DNA. The gene therapy carries a gene sequence to replace it, targeting the liver cells and releasing the genetic material. The body then reads the gene sequence and makes a copy of the enzyme that can break down the phenylalanine.

We are in an exciting period of genomic medicine, exploring the ability to help correct genetic diseases, said Dr. Adams. We are hopeful that the success of this gene therapy will be the doorway to solving many more common health disorders.

Dr. Adamss colleagues throughout at Atlantic Health System are enthusiastically supportive of his participation in the trial.

At Goryeb Childrens Hospital and Childrens Health throughout Atlantic Health System, we strive to make patients lives healthier from the very earliest stages of childhood, said Walter Rosenfeld, MD, chair of pediatrics. While this initial trial involved an adult, its success offers great hope to parents and patients of all ages as an important new tool that could have a huge impact on their lives.

The Jacobs Levy Genomic Medicine and Research Program at Atlantic Health System provides individualized, full-spectrum genomic care, designed to ensure that patients receive the medical and health services that will most benefit them.

This includes diagnostic testing based on symptoms, family history and result consultation with a licensed genetic counselor to thoroughly explain positive results and discuss further medical care options. For chronic patients, care includes follow up visits, blood level monitoring and medication management.

The genomic program treats and follows numerous patients diagnosed with PKU, with doctors and a dietitian helping them to closely monitor and track their level of phenylalanine, maintain their dietary modifications and prescribe injectable treatment.

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Patient at Atlantic Health Receives First US Dose for New Gene Therapy - njbmagazine.com

Patients withgeneticlysosomal storagediseases particularly children are living longer because of better treatments. But with promising advances and longer lives comes complications, the loss of eyesight as these rare diseases take their toll over time.

Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the bodys cells as a result of enzyme deficiencies, according to theNational Organization for Rare Disorders. With these diseases, patients are missing the mucopolysaccharidosis type 1 (MPS1) gene. Current therapies that allow patients to live longer dont address corneal clouding caused by these diseases. However, one Carolina-affiliated startup, RainBio, isdeveloping anovel gene therapyforMPSI corneal blindness, giving patients a chance not only for longer lives but better ones.

The companys treatment, RBIO-1, is poised to meet a large unmet medical need in ophthalmology.Co-foundedbyMatt Hirsch,associate professor of ophthalmology at the UNC Gene Therapy Center, RainBio is the only ocular gene therapy pioneer focused on blindness in the cornea. The companys adeno-associated virus vector gene therapy can directly correct cornea cellular function to maintain or restore vision in patients at risk of blindness. The companys first candidate is a groundbreaking, first-in-class lead program for corneal clouding in MPS1 patients who have vision loss.

As we look at what is being done in the ophthalmology space, we see that most [adeno-associated virus] therapeutics are focused on the back of the eye the retina, but nobody seems to be looking at the front of the eye the cornea, says Fran Martin, RainBio president. If we can provide those affected with lysosomal storage diseases a mechanism where they can see, theyd be able to have a better quality of life.

The idea for RainBios treatment started less than five years ago, when Dr. Joanne Kurtzberg, a pediatric bone marrow transplant specialist, who conducts stem cell transplants in children with lysosomal storage diseases at Duke, met with Hirsch and Samulski to figure out how to potentially address the blindness that comes with lysosomal storage disease. Kurtzberg works with stem cell therapies that can extend the longevity of life for kids affected but dont address the loss of sight. Hirsch realized if he could replace the missing gene in the cornea, those kids could regain their sight.

With our product, you inject the missing gene right into the cornea, says Martin. This allows for prevention of corneal clouding or blindness, and can even reverse the blindness or cornea clouding if the treatment is given early enough.

For kids who are losing their sight, another option is to have a cornea transplant. But those transplants dont come without risk.

Corneal transplants can sometimes result in high rejection rates and potential infection, adds Martin. We can offer an additional treatment that patients can try before moving to a transplant.

The RainBio team often collaborates with colleagues at local universities as well asJoseph Muenzer,a professor of pediatric genetics and metabolism at the School of Medicine, who treats children affected bylysosomal storage diseases.Jude Samulski, professor of pharmacology at the Gene Therapy Center in the UNC School of Medicine and a pioneer in gene therapy, also contributed to the patents for the product.

A lot of expertise in gene therapy was developed over the past few decades at UNC, says Martin. That expertise has benefited RainBio, and weve benefited from the input into the science around our product as well.

To make the best use of resources, the RainBio team benefits from collaborating withKickStart Venture Services as well as Carolinas Office of Technology Commercialization. KickStart supports faculty startup formation, business development and growth by providing coaching and mentoring, early-stage funding, connection with key service providers, management, investors and space. Both KickStart and the Office of Technology Commercialization. are part of Innovate Carolina, the University-wide initiative for innovation and entrepreneurship.

Its been a pleasure to work with KickStart and OTC to really get the guidance and resources needed as weve grown as a company, says Martin. They helped us work through the Carolina Express License and have been very supportive in helping us to understand the process as well as in providing resources as we think through our strategy as a growing company.

The Carolina Express license assists Carolina startups by streamlining and speeding the path for UNC-Chapel Hill faculty, students or staff startup founders to translate new discoveries into useful products.

Alongside Epigenos Bioscience, the RainBio team also had the opportunity in fall 2020 to present to approximately 20 advisors who gave them advice on how to continue commercializing their technology and growing their business, even in the midst of a pandemic. This is one of the programs that Kickstart adapted online to continue providing support for startups. Advice and guidance offered at advisory meetings includes anything from R&D to fundraising and strategy. Other startup companies that would like to present can get in touch with KickStart to be considered for a future meeting.

In addition, RainBio received a $100,000 loan fromNCBiotechas well as support from theMPS Society, which funded a key rabbit toxicology study. RainBio also collaborated with NC State University through co-founderBrian Gilger, who has conducted the toxicology studies at the NC State School of Veterinary Medicine.

And for patients who are ready to try RainBiosRBIO-1 treatment,Martin says the idea of a one-time dose is promising.

Although we are still testing the product, whats also unique about this treatment is that only one dose may be required. In addition, a very small amount of product around 250 times less will be needed compared to other treatments on the market for retinal blindness, she adds.

Although the company only launched in June 2020, RainBio already has pre-clinical efficacy and safety data and is poised to meet with the US Food and Drug Administration.

Even though were not even a year old, we have orphan drug designation and rare pediatric disease designation that was granted to us by the FDA, says Martin. We have pre-clinical efficacy in theMPS1canine model, and 100 percent prevention and reversal of cornea blindness.

RainBio is developing aplatform for additional treatmentsfor blinding corneal diseases.

There are several Lysosomal storage diseases that have the same cornea blindness issue, says Martin. Although its a different gene that is missing, we believe as we prove this concept inMPS1patients, then it will be translatable to otherlysosomal storagediseases.

As RainBio continues to grow and develop its product, next steps include accessing additional funding to manufacture the product and get it into the clinic.

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Breakthrough gene therapies in sight | UNC-Chapel Hill - UNC Chapell Hill

BOSTON Thomas Feldborg and Daria Rokina set off nearly every afternoon to explore this city. They leave from theirhotel in theCharlestown neighborhood, pushing theirbaby carriage, some days heading deep into downtown, others choosing a path along the Charles River.

Every few minutes, Rokina stopsto peek inside and check on 16-month-old Alissa. Shegently rubs Alissa'scheek and coos a few soothing words, makingsure the little girl is warm enough in her yellow snowsuit and adjusting hersparkly unicorn earmuffs.

Alissa restsbetter in the outside air. Thedaily walksallowthecoupleto relieve some of the stress of notknowing whether their daughter will survive and if so,in what condition.

Feldborg, 50, has three older sons, and Rokina, 43, has one. Alissa, their first child together,was born Dec. 2, 2019, in Copenhagen, Denmark,where the family lives.For her first four months of life, Alissaseemed perfectly normal. She learned to roll and sit up. She babbledand grabbedfor toys.

Then her progress began to stall. By six months when Alissa wasn't trying to crawl, Rokina took her to the pediatrician. Children advance at their own pace, the doctorassured her. Nothing was wrong.

At eight months, the trouble became impossible to ignore. Alissa was hospitalized, dehydrated and unable to eat. A neurological exam turned up cherry red spots atthe back of her eyes, a devastating observation in a baby, because it indicates one of a few genetic disorders, most terrible and deadly before age5.

New hope for 16-month-old battling rare, fatal genetic disorder with gene therapy

Alissa Feldborg is 16 months old and is undergoing gene therapy for Sandhoff disease, a very rare, fatal genetic disorder.

Robert Deutsch, USA TODAY

Feldborg immediatelystarted Googling.Before Alissa received the diagnosis of Sandhoff disease, an extremely rarecondition, he already had stumbled across the idea of gene therapy. If they could just repair the faulty gene Alissa inherited from him and Rokina, she might have a shot at life.

That internet research led the couple to the University of Massachusetts, where in late January, Alissa, then nearly 14months old,became the first child in the world to receive a full dose of a new gene therapy. If it worked, it would trigger the cells in her brain to start making theenzyme they had been missing,clearing out cellular debris, so they can function normally.

CHOOSING HOPE

The first in an occasional series exploring how scientific advancesare transforming care for rare diseases.

Gene therapy like Alissa's a scientific vision for decadesis finally becoming a more common reality in the United States.

Dozens of disorders are now being treated, though most still only in clinical trials, like Alissa's. Within the next few years, experts say, gene therapies could soon be available for conditions never effectively treatable before,such as sickle cell disease, Huntington's, ALS, Parkinson's, some formsof heart disease and a host of very rare diseases.

"The exponential growth phase" of gene therapy has arrived, saidDr. Cynthia Tifft,director of the Pediatric Undiagnosed Diseases Program atthe National Institutes of Health.

"Finally, after literally decades of hearing it was just around the corner, we are witnessing some real successes," said Dr.Isaac Kohane,chair of the Department of Biomedical Informatics atHarvard Medical School and head of the federally funded Coordinating Center for the Undiagnosed Diseases Network.

At their best, gene therapies offer the possibility of a cure,truly reversing the root cause of a disease.

But as simple as the idea seems just fixing a DNA typo it is incredibly difficult to turn into an actual therapy. Scientists so far have spent decades on each step in the process.

And with such a new procedure, aimed athaving lifelong benefits, it's too early to know whether these approaches will change a child's trajectory, allow an adult to live without fear and pain,or prevent a disease from evercoming back.

"People are underestimating what it's going to take to make (gene therapy) work in the short term,"Kohane said,"and under-appreciating how transformative it will be in the long term."

On her first birthday, Dec. 2, 2020, Alissa received a colorful book and toy. She grabbed for both, excited to reach them.

But by the end of themonth, she could no longer make that simple movement. She could barely hold up her head and slipped into silence.Seizures accelerated the regression.

"She went more into herself … she was not very present anymore,"Feldborg said.

He and Rokina felt totally alone deciding whether to pursue the treatmentfor Alissa. Two other babies had similar procedures with a lower gene therapy dose, but medical privacy laws prevented the couple from speaking with their parents.

There was no doubtwhat would happen if they did nothing.

Parents of 16-month-old Alissa Rokina Feldborg, Daria Rokina and Thomas Feldborg on April 13, 2021 in Arlington, Mass.Robert Deutsch, USA TODAY

For babies with Alissa'sdisorder and a "cousin" condition called Tay-Sachs disease, "their quality of life is essentially vegetative," Tifft said. Feeding tubes and other supportive care can keep them alive for a while.But they all die by the time they should be entering kindergarten.

So, as Feldborg said, the pairdecided to "lethope conquer the fears." It was simply too awful to watch her decline without trying anything when they were among the first families in history who could try something.

But even as he and Rokina packed and boarded a plane for the U.S. in early January, theywere tormented by the idea that the therapy might onlykeep Alissa alive longer in the same miserable state.

"Instead of having this cruel, short life of two, three, maybe four years, maybe she will just have a cruel, long life," Feldborg said,while walking through a park on a brisk, early spring afternoon. "That's what we were fearing."

On Jan. 26, after weeks of testing to make sure she was still a good candidate and prepare her for the procedure, Alissa was wheeled into an operating room atUMass Memorial Medical Center in nearby Worcester for brain surgery.

Researchers felt that the best way to unclog her brain cells was to inject the gene therapy directly into her thalamus, two oval structuresdeep inside the brain that actas sort of a highway junction, connecting paths from many parts of the brain. Doctors used an image-guided robotic arm to ensure it got to the right spot.

The next day, the same gene therapy was infused into the fluid aroundher spinal cord so it could penetratethe nerves there.

If it worked as planned, the added geneswould instruct cells throughout her nervous system and brain to start producing the missing enzyme.

"You don't actually need a lot of enzyme activity in order for the neurons to function better," said Dr. Pavan Cheruvu, CEO of Sio Gene Therapies, the New York-based biotech company running the trial and paying the full cost of Alissa's treatment and her parents' stay in the U.S.

One previous child had received the thalamic surgery, butthere wasn't enough of the therapy available to give hera full dose. So far, her condition has been stable at a time when most kids with the condition decline, said Dr. Terence Flotte, dean of theUMass Medical School, who is leading Alissa's trial. Another child got the spinal injection but not the thalamic one.

Alissa was the first to get a full dose in both places.Later patients in the trial will get an even higher dose. Feldborg and Rokina hopeAlissa got enough to make a profound and positive difference in the course of her life.

But for now, all they can do is wait. And walk.

Thomas Feldborg and wife Daria Rokina carry their daughter Alissa Rokina Feldborg, 16 months old, home from a therapy session on April 13, 2021 in Arlington, Mass.Robert Deutsch, USA TODAY

About 45 minutes west of Boston, a herd of Jacobsheep live in a series of pens overlooking rolling hills.

Guarded by a llama and an electric fence, both to keep coyotes away, several sheep pause to stare at strangers at the Cummings School of Veterinary Medicine at Tufts University where they live. Then they boltoff.

These 110 sheep are the descendants of a pairthat once lived on a Texas farm. In 1999, twolambs began stumbling and tripping. They developed seizures, lost sight and had trouble swallowing before dying young.OwnersFred and Joan Horak wanted to understand why.

It took a decade for a researcher from New York University Medical Center, nowNYU Langone Health,to figureout the sheep carried the same genetic mutation that causes Tay-Sachs disease. Researchers later learned cats also can inherit a similar genetic mutation.

Finding an animal model in which adisease naturally occurs is extremely helpful for developing treatments, said Douglas Martin, a professor at theAuburn University College of Veterinary Medicine in Alabamawho studies these conditions in house cats.

In animals, researcherstested and refined the virusthat eventually deliveredAlissa's gene therapy.

Stephanie Bertrand, assistant farm manager at Cummings School Farm at Cummings School of Veterinary Medicine at Tufts University, provides care for the Jacob sheep that are integral to the research being led by University of Massachusetts Medical School. Photo credit: Matthew Healey for Tufts University.Matthew Healey, Matthew Healey for Tufts University

Gene therapies are often transportedinto cells by viruses similar to howpathogens are usedto deliver the COVID-19 vaccines madeby Johnson & Johnson and AstraZeneca-Oxford University. It's taken decades to find the appropriateviruses and engineer them to safely deliver genes or editing tools.

In Alissa's trial, a virus carries DNA instructions for making the missing enzyme. Designed by Miguel Sena-Esteves, aUMass Medical School researcher who has been working on the project for more than a decade, the therapy delivers two genes, even though Alissa is only missing one. Animal studies showed that adding both the gene that causes Tay-Sachs plus a nearbyone that causes Sandhoff provides the best results for children with both conditions.

Alissa'sown DNA isn't changed in this approach, though other gene therapies rely on gene editing to altercells'DNA code.

Her immune system is kept tamped down with medication so that, if needed, she can be dosed again with the virus-carrying gene therapy, Flotte said.

Lena Labdi, a research assistant at the University of Massachusetts Medical School in Worcester, examining slides in the Sena-Esteves lab on April 13, 2021.Robert Deutsch, USA TODAY

Researchers have tried beforeto treat both conditions by providing the missing enzyme instead of adding genes, but it is too big to cross from the bloodstream into the brain.

By 2012, Sena-Esteves had shown that the virus and gene therapy worked in mice;Martin, at Auburn, provedthe samein cats, anda third colleague, HeatherGray-Edwards, now of UMass Medical School,used it to rescueJacob sheep.

Just before trying the approach in children, the team decided to test it in monkeys. The Food and Drug Administration probably wouldn't have required it after their success in other animals, but they wanted to be extra cautious.

The results were devastating. The monkeys became apathetic and lostdexterity, Edwards said. They clearly weren't helped.

It took years of research to figure out thatthe animalshad gotten too much of a good thing: The extra enzymes that helped cleanup the brain cells of other mammals was overwhelming and killing the monkey's cells.

Sena-Esteves said the day helearnedthe resultswas perhaps the worst of his professional life. Butit was far better to learn the lesson on monkeys.

The therapy given to childreniscarefully calibratedin hopes of achievinga Goldilocks balance: not too little, but not too much.

Lena Labdi, a research assistant at the University of Massachusetts Medical School, working in the Sena-Esteves lab on April 13, 2021, in Worcester, Mass.Robert Deutsch, USA TODAY

Last year, Feldborg and Rokina, both now on paid leave from their sales and logistics jobs, befriended the other two Danish families whosebabies had beendiagnosed with Sandhoff.

One child was two months older than Alissa, the other eight months older. Neither got gene therapy. Bothdied earlier this year.

Doctors selected Alissa for the trial hoping she was still young enough andher losses recent enoughthat the damage to her brain might be reversible.

"We think that there are many cells that are simply under duress" due to the toxic build-up of fats, said Dr. Florian Eichler, a pediatric neurologist at Massachusetts General Hospitalwho treatsAlissa. "If we can appropriately return a healthy copy of the gene and the enzyme, that cell can recover."

Last fall, watching their daughter slip further away, Feldborg and Rokina worried that Alissawould be disqualified from the trial because shehad already lost too much function, or that thetreatment would come too late to make a difference.

Alissa Feldborg receives treatment from Feldenkrais practitioner Matthew Wilkinson while dad Thomas and mom Daria watch on April 13, 2021 in Arlington, Mass.Robert Deutsch, USA TODAY

Doctors warned them not to expect much. No one knewifthe therapy would help or how long it might take to start seeing changes.

But just a weekafter the surgeries, Alissa's sparkling blueeyes, which had been rolling randomly and constantly, seemed to stabilize andfocus. With eyes in constant motion, she couldn't have been ableto see much.

Now that they're more focused, it's also easier to feel like there's someone present behind them.

In February, Alissa started to move her hands with some intentionandbegan eating more. Swallowing was the one skill she hadn't lost, but perhaps because of the steroids that are part of her careshebecame hungry again, accepting spoonfulsof soft food. Recently, shelearned how to suck downa bottle for the first time.

"If this development will continue, we are just so very happy," Rokina said."It'sso nice."

There also was a wonderful surprise. About two weeks after her surgeries, Alissa started smiling again. Not in response to the outside world, but to some internal moment of pleasure or humor.

A few days after that, she laughed a deep, guttural belly laugh. Feldborg said he can count on one hand the number of timesshe had laughed like that before the procedure. But for the last few weeks, she has enjoyed a private laugh nearly every day.

The sound of those belly laughshas been a gift, a balm.

The first time it happened, while giving hera bath,Feldborg said,"Wewere so happy, we just kissed each other like we had become world champions in our favorite sports."

To compensate for her lack of sight and hearing, Rokina and Feldborg tryto offerAlissa some connection to the worldthrough touch.

Rokina,a native of Russia, grew up with the tradition of giving babies massages. Before Alissa's gene therapy, months of massages and movement therapy had done little except perhapsallowher to keep swallowing.

After the surgeries, Feldborg and Rokinarenewed the practice, drivingAlissa once a week to baby massage sessions in a far-flung Boston suburb, andtwo or three mornings a week to the closer-in town of Arlington, where Matty Wilkinson triesto reconnect the little girl's brain to the body she can do so little with.

Wilkinson, who has a master's degree in child development as well as training inthe Feldenkrais Methodand the Anat Baniel Method for Children, uses small movements aimed atteaching Alissa'sbrain to once again sense her neck, arms, legs, pelvis and spine.

Feldenkrais practitioner Matthew Wilkinson provides treatment to 16-month-old Alissa while dad Thomas Feldborg and mom Daria Rokina watch on April 13, 2021 in Arlington, Mass.Robert Deutsch, USA TODAY

"She's having to rebuild a map of herself, how she can interact with her environment," he said after a recent session. "I'm trying to make the information clearer and more distinct, so she can perceive those feelings … so she can gain more choice."

Laying Alissa on her side, Wilkinson pulls gently on her left arm while touching the back of the same shoulder. She occasionally moves her mouth in a sucking motion, but otherwise lies still.

One of the first truly successful gene therapies, for a condition called spinal muscular atrophy,showed that the treatment, while immensely effective, wasn't enough on its own. Just as newborns learn to control their limbs by moving them, so children whose brains have lost the ability todirect movement ornever developed it in the first place need practice for the proper wiring to form.

"We say with the nervous system, you have to use it or you lose it," Eichler said. "There has to be continued stimulation, activity, and so all of those things Alissa's parents do so well with her are vital."

People tell Feldborg how "brave" he and his wife are for trying gene therapywith Alissa. He's not sure how to respond.

"There's a fine line between bravery and stupidity," he said. "Are we so stupid in our hope? Is it a fool's mission we're on?"

This past week,three months after her surgery, doctors began a battery of tests on Alissa to see if they can detect objective signs ofprogress. They're hoping to see evidence on herMRI scan that her brain is repairing itself.

The trial would be deemed successful if it achieved any of three possible outcomes, said the NIH's Tifft: It could slow Alissa's decline, keep her from slipping any furtheror actually help her gain skills.

"None of these children ever improve on their own. They just don't," Tifft said."In a disease that only progresses downhill, even preserving function is a win."

"Then the question is, for how long," she added.

No matter what happens, the trial represents "a huge milestone" in the treatment of Sandhoff and related diseases,Eichler said.

Tay-Sachs wasidentified more than a century ago.The chemistry of whatitand Sandhoff do to the brain has been understood for at least half that time. Now,the gene deficit itself can finallybeaddressed, Eichler said.

Still, a lotto be learnedabout the best timing for the therapy, what cells need to be targeted andwhat meaningful change looks like.

"That is the nature of progress. If we knew what works, we wouldn't need to conduct trials," Eichler said."I feel for the parents."

For their part, Feldborg and Rokina say they hope the trial will help others, but are realistic about what might be achievable for themselves. They know Alissa will never be like other children. They just want a daughter they can communicate with in some way.

"She can be in a wheelchair or whatever," Feldborgsaid, "but if we don't get a thinking person out of this,that's where I think we may have been more stupid than brave."

Contact Karen Weintraub at kweintraub@usatoday.com.

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

Excerpt from:
An experimental gene therapy was little Alissa's only hope. Now, instead of certain death, she faces an uncertain future. - USA TODAY

Dive Brief:

BioMarin, a California biotech that built its business around drugs for rare diseases, is a leading gene therapy developer. The Food and Drug Administration reviewed the company's treatment for hemophilia A last year and,while the agency unexpectedly rejectedits application, many expect the regulator to eventually approve the therapy once BioMarin has more follow-up data in hand.

The drugmaker also has gene therapies in earlier stages of testing for a metabolic condition known in shorthand as PKU and a rare disease called hereditary angioedema.

But BioMarin has also been exploring gene therapy for diseases of the central nervous system, although it hasn't publicly commented on its work in the space until Wednesday's announcement of the deal with the Allen Institute.

While targeting CNS diseases presents its own challenges, particularly around delivery of treatment, many gene therapy developers are nonetheless working on would-be therapies. According to a count by Cowen, an investment bank, a third of all disclosed preclinical or clinical gene therapy programs as of January 2021 were in neurology, which encompasses more prevalent diseases like Parkinson's as well as rarer conditions like ALS and Huntington's.

For BioMarin, the Allen Institute could provide a better tool to target some of these diseases. Adeno-associated viruses are a common delivery tool for gene therapy, but the technology is decades old and has limitations. Several biotech startups, as well as academic laboratories and groups like the Allen Institute, have been researching how to improve the usefulness of AAVs.

Under Wednesday's deal, scientists from BioMarin and the Allen Institute will work together to evaluate the nonprofit's modified AAVsfor potential use in building more precise CNS-targeted therapies.

"Combining the Allen Institute's leadership in large-scale genomic science in the central nervous system with BioMarin's proven experience in developing transformational therapies for rare genetic diseases, lays the foundation to potentially deliver multiple investigational gene therapies to the clinic," said Lon Cardon, BioMarin's chief scientific strategy officer, in a statement.

The research behind the Allen Institute's work on modified AAVs was published last month in the journals Neuron and Cell Reports.

Originally posted here:
BioMarin partners with Allen Institute to develop gene therapies for the brain - BioPharma Dive